2,8-disubstituted naphthyridine derivatives

ABSTRACT

Disclosed are compounds of formula A: 
                         
and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, R 3 , R 21 , A 1 , A 2 , X, and Z are as defined herein. Compounds of formula A are useful in the treatment of diseases and/or conditions related to cell differentiation, such as cancer, inflammation, arthritis, angiogenesis, or the like. Also disclosed are pharmaceutical compositions comprising compounds of the invention and methods of treating the aforementioned conditions using such compounds.

BACKGROUND OF THE INVENTION

This application claims priority from U.S. Provisional Application No.60/598,518, filed Aug. 3, 2004, the disclosure of which is incorporatedherein in its entirety.

FIELD OF THE INVENTION

The invention relates to 2,8-disubstituted naphthyridines and morespecifically to such compounds that are useful in the treatment and/orprevention of diseases and/or conditions related to celldifferentiation, such as cancer, inflammation andinflammation-associated disorders, and conditions associated withangiogenesis.

DESCRIPTION OF THE RELATED ART

Angiogenesis is a highly regulated process under normal conditions,however many diseases are driven by persistent unregulated angiogenesis.Unregulated angiogenesis may either cause a particular disease directlyor exacerbate an existing pathological condition. For example, ocularneovascularization has not only been implicated as the most common causeof blindness, but also is believed the dominant cause of many eyediseases. Further, in certain existing conditions, for examplearthritis, newly formed capillary blood vessels invade the joints anddestroy cartilage, or in the case of diabetes, new capillaries formed inthe retina invade the vitreous, bleed, and cause blindness. Growth andmetastasis of solid tumors are also dependent on angiogenesis (Folkman,J., Cancer Research, 46, 467-473 (1986), Folkman, J., Journal of theNational Cancer Institute, 82, 4-6 (1989). It has been shown, forexample, that tumors which enlarge to greater than 2 mm must obtaintheir own blood supply and do so by inducing the growth of new capillaryblood vessels. Once these new blood vessels become embedded in thetumor, they provide a means for tumor cells to enter the circulation andmetastasize to distant sites such as liver, lung or bone (Weidner, N.,et al., The New England Journal of Medicine, 324(1), 1-8 (1991). Underconditions of unregulated angiogenesis, therapeutic methods designed tocontrol, repress, and/or inhibit angiogenesis could lead to theabrogation or mitigation of these conditions and diseases.

Cancer is characterized by abnormal cellular proliferation. Cancer cellsexhibit a number of properties that make them dangerous to the host,typically including an ability to invade other tissues and to inducecapillary ingrowth, which assures that the proliferating cancer cellshave an adequate supply of blood. A hallmark of cancerous cells is theirabnormal response to control mechanisms that regulate cell division innormal cells and continue to divide until they ultimately kill the host.

Inflammation is related to a variety of disorders such as pain,headaches, fever, arthritis, asthma, bronchitis, menstrual cramps,tendinitis, bursitis, psoriasis, eczema, burns, dermatitis, inflammatorybowel syndrome, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, vascular diseases, Hodgkin's disease, sclerodoma,rheumatic fever, type I diabetes, myasthenia gravis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, hypersensitivity,conjunctivitis, gingivitis, post-injury swelling, myocardial ischemia,and the like.

Therefore, there is a continuing need in the art for new methods oftreating cancer, inflammation and inflammation-associated disorders, andconditions or diseases related to uncontrolled angiogenesis.

U.S. Pat. No. 5,945,431 discloses heterocyclic compounds of the formula(I):

wherein

-   -   W is selected from CH, CR₃, CH₂, C═O, CHR₃, N and NR₅; one of X,        Y, and Z is N or NR₅ while the other two are independently        selected from CH, CR₄, CH₂, C═O and CHR₄;    -   B is selected from the group consisting of

wherein

-   -   A is O or S;    -   R₁ is selected from:        -   C₁₋₆ alkyl, C₂₋₆ alkenyl or C₃₋₇ cycloalkyl, each of which            is optionally substituted with OH, halogen, amino, carboxyl            or saturated or unsaturated C₃₋₁₀ (carbocycle or            heterocycle) optionally substituted with OH, halogen, amino,            mercapto, carboxy, C₁₋₄ (alkyl, alkoxy, alkylthio, acyl,            acyloxy or alkoxycarbonyl) optionally substituted with OH,            halogen, amino or C₁₋₄ alkoxy,; and        -   C₃₋₇ cycloalkyl fused to C₆₋₁₀ aryl optionally substituted            with OH, halogen, amino, mercapto, carboxy, C₁₋₄ (alkyl,            alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl)            optionally substituted with OH, halogen, amino or C₁₋₄            alkoxy;    -   R₂ and R′₂ are independently H, C₁₋₄ alkyl or R₁ and R₂ together        form a saturated or unsaturated 5 or 6 member heterocycle        optionally fused to C₆₋₁₀ aryl or heteroaryl;    -   R₃ and R₄ are independently selected from H, OH, halogen, amino,        cyano, C₁₋₆ (alkyl, alkoxy, acyl, acyloxy or alkoxycarbonyl),        where each alkyl and acyl portion is optionally substituted with        OH, halogen, amino or C₁₋₄ alkoxy, and saturated or unsaturated        C₃₋₁₀ (carbocycle or heterocycle) optionally substituted with        OH, halogen, amino, mercapto, C₁₋₄ alkylthio, C₁₋₄        alkoxycarbonyl, halo substituted C₁₋₄ alkyl or halo-substituted        C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or carboxy;    -   R₅ is H, C₁₋₆ alkyl or C₁₋₆ acyl, where each of the alkyl and        acyl is optionally substituted with OH, halogen, amino or C₁₋₄        alkoxy; and    -   n is 0, 1 or 2.

U.S. Pat. No. 5,945,431 discloses how to make the above compounds andhow to use them allegedly as cytomegalovirus (CMV) inhibitors for thetreatment of conditions related to CMV infection in mammals. Thedisclosure of U.S. Pat. No. 5,945,431 is incorporated herein byreference in its entirety.

SUMMARY OF THE INVENTION

In a broad aspect, the invention encompasses the compounds of formula Ashown below, pharmaceutical compositions containing those compounds andmethods employing such compounds or compositions in the treatment ofdiseases and/or conditions related to cell differentiation, such ascancer, inflammation, arthritis, angiogenesis, or the like.

The invention provides compounds of formula A, hereinafter “Embodiment1”:

or pharmaceutically acceptable salts thereof, wherein each

independently represents a single bond or a double bond;

-   A₁ is N, or an N-oxide;-   A₂ is N, an N-oxide, NH, or N(C₁-C₆) alkyl; provided that when    is a single bond, then A₂ is NH, or N(C₁-C₆) alkyl;-   X is —NR_(x)R_(y), or —C(O)R₂₀; wherein    -   R_(x) and R_(y) are independently H, C₁-C₆ alkyl,        alkoxycarbonyl, arylalkoxycarbonyl, aryl, arylalkyl, —C(O)-aryl,        heteroaryl, heteroarylalkyl, or —C(O)heteroaryl, wherein the        aryl and heteroaryl rings are optionally substituted with 1, 2,        3, 4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆        alkoxy, halogen, CO₂H, NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇,        —(C₁-C₄ alkyl)-C(O)NR₆R₇, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy;-   Z is a bond, —CH₂—, —NH—, —O—, —N(C₁-C₆ alkyl)-, —S—, —S(O)—, —SO₂—,    —SO₂NH—, or —SO₂N(C₁-C₆ alkyl)-;-   R₁ is halogen, C₁-C₆ alkanoyl, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆    alkenyl, aryl, heteroaryl, heterocycloalkyl, or C₃-C₈ cycloalkyl,    each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄    alkyl)-NR₆R₇, —C(O)NR₆R₇, heteroaryl, heterocycloalkyl, phenyl, or    naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl and    naphthyl groups are optionally substituted with 1 or more groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, OH, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); or    -   R₆ and R₇ and the nitrogen to which they are attached form a        ring having from 5 to 8 members, wherein the ring optionally        contains 1-3 additional heteroatoms selected from N, O, and S,        where the ring is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,        amino, NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);    -   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl, or        cycloalkyl, wherein the cyclic portions are optionally        substituted with 1, 2, or 3 groups that are independently        halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄        haloalkyl, or C₁-C₄ haloalkoxy;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₁        and R₁₀ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃;-   R₂, R₂′, and R₃ at each occurrence are independently H, halogen,    C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, —C(O)NH₂, —C(O)NH(C₁-C₆    alkyl), —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl), or aryl;-   R₂₀ is H, OH, C₁-C₆ alkoxy, or NR₄R₅; wherein    -   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆        alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl,        cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl,        heterocycloalkyl, heterocycloalkylalkyl,        heterocycloalkylalkenyl, heterocycloalkylalkynyl, aryl,        heteroaryl, heteroarylalkyl, heteroarylalkenyl,        heteroarylalkynyl, arylalkyl, arylalkenyl, or arylalkynyl,        wherein the cyclic portion of each of the above is unsubstituted        or substituted with one or more groups that are independently        C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄        haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, aryl C₁-C₆ alkyl,        C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,        NR₇R₈, or —C(O)NR₇R₈,        -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl,            wherein the alkyl is optionally substituted with 1, 2, or 3            groups that are independently C₁-C₆ alkoxycarbonyl, halogen,            C₁-C₆ alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆            alkyl)(C₁-C₆ alkyl) or CO₂H; or        -   R₇ and R₈ and the nitrogen to which they are attached form a            ring having from 5 to 8 members, wherein the ring optionally            contains 1-3 additional heteroatoms selected from N, O, and            S, where the ring is optionally substituted with 1, 2, or 3            groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, OH,            halogen, amino, NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆            alkyl);        -   wherein the heterocycloalkyl and the cycloalkyl portions of            R₄ and R₅ are further optionally substituted with ═O, ═N—OH,            or ═N—OCH₃; or    -   R₄ and R₅ and the nitrogen to which they are attached form a        heterocycloalkyl ring, which is unsubstituted or substituted        with 1 or more groups that are independently C₁-C₆ alkyl, C₁-C₆        alkoxy, halogen, aryl C₁-C₆ alkyl, C₁-C₆ alkanoyl, OH, ═O,        heteroaryl, heteroarylalkyl, phenyl, naphthyl, —OCH₂CH₂O—,        —OCH₂O—,        -   wherein the heteroaryl, phenyl and naphthyl groups are            unsubstituted or substituted with 1 or more groups that are            independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃ or            OCF₃;-   R₂₁ is H, CN, amino, monoalkylamino, dialkylamino, OH, halogen, aryl    (phenyl or naphthyl each of which is optionally substituted with 1-5    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or    haloalkoxy (in one aspect, OCF₃)), or heteroaryl (pyridyl,    pyrimidyl, indolyl, or (iso)quinolinyl, each of which is optionally    substituted with 1-5 groups that are independently C₁-C₆ alkyl,    C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one    aspect, CF₃), or haloalkoxy (in one aspect, OCF₃) ), C₁-C₆ alkyl,    C₂-C₆ alkynyl, C₂-C₆ alkenyl, —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), or    —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl);    provided that R₁ is halogen only when Z is a bond;    provided that when-   R₂₀ is NR₄R₅ and R₄ is C₁₋₆ alkyl, C₂₋₆ alkenyl or C₃₋₇ cycloalkyl    optionally substituted with OH, halogen, amino, carboxyl or    saturated or unsaturated C₃₋₁₀ (carbocycle or heterocycle)    optionally substituted with OH, halogen, amino, mercapto, carboxy,    C₁₋₄ (alkyl, alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl)    optionally substituted with OH, halogen, amino or C₁₋₄ alkoxy; and    C₃₋₇ cycloalkyl fused to C₆₋₁₀ aryl optionally substituted with OH,    halogen, amino, mercapto, carboxy, C₁₋₄ (alkyl, alkoxy, alkylthio,    acyl, acyloxy or alkoxycarbonyl) optionally substituted with OH,    halogen, amino or C₁₋₄ alkoxy;-   R₅ is H, or C₁₋₄ alkyl; and-   (1) Z is a bond; and-   R₂ or R₃ is H, OH, halogen, amino, cyano, C₁₋₆ (alkyl, alkoxy, acyl,    acyloxy or alkoxycarbonyl) optionally substituted with OH, halogen,    amino or C₁₋₄ alkoxy, and saturated or unsaturated C₃₋₁₀ (carbocycle    or heterocycle) optionally substituted with OH, halogen, amino,    mercapto, C₁₋₄ alkylthio, C₁₋₄ alkoxycarbonyl, halo substituted C₁₋₄    alkyl or halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or    carboxy; or-   (2) Z is a bond;-   R₂ or R₃ is H, OH, halogen, amino, cyano, C₁₋₆ (alkyl, alkoxy, acyl,    acyloxy or alkoxycarbonyl) optionally substituted with OH, halogen,    amino or C₁₋₄ alkoxy, and saturated or unsaturated C₃₋₁₀ (carbocycle    or heterocycle) optionally substituted with OH, halogen, amino,    mercapto, C₁₋₄ alkylthio, C₁₋₄ alkoxycarbonyl, halo substituted C₁₋₄    alkyl or halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or    carboxy; and-   R₄ and R₅ together form a saturated or unsaturated 5 or 6 member    heterocycle optionally fused to C₆₋₁₀ aryl or heteroaryl; then-   R₁ is not OH, halogen, amino, cyano, C₁₋₆ (alkyl, alkoxy, acyl,    acyloxy or alkoxycarbonyl) optionally substituted with OH, halogen,    amino or C₁₋₄ alkoxy, and saturated or unsaturated C₃₋₁₀ (carbocycle    or heterocycle) optionally substituted with OH, halogen, amino,    mercapto, C₁₋₄ alkylthio, C₁₋₄ alkoxycarbonyl, halo substituted C₁₋₄    alkyl or halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or    carboxy.

The invention also includes intermediates that are useful in making thecompounds of the invention.

The invention also provides pharmaceutical compositions comprising acompound or pharmaceutically acceptable salt of formula A and at leastone pharmaceutically acceptable carrier, solvent, adjuvant or diluent.

The invention further provides methods of treating disease such ascancer, inflammation, arthritis, and angiogenesis in a patient in needof such treatment, comprising administering to the patient a compound orpharmaceutically acceptable salt of formula A, or a pharmaceuticalcomposition comprising a compound or salt of formula A.

The invention also provides the use of a compound or salt according toformula A for the manufacture of a medicament for use in treatingcancer, inflammation, arthritis, or angiogenesis.

The invention also provides methods of preparing the compounds of theinvention and the intermediates used in those methods.

The invention further provides a compound or pharmaceutical compositionthereof in a kit with instructions for using he compound or composition.

DETAILED DESCRIPTION OF THE INVENTION

Preferred compounds of formula I include compounds of embodiment 2,i.e., compounds of Formula A wherein,

-   R₁ is halogen, C₁-C₆ alkanoyl, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆    alkenyl, phenyl, naphthyl, thienyl, furanyl, indolyl, pyridyl,    pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl,    isoxazolyl, benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl,    piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl,    thiomorpholinyl, S,S-dioxothiomorpholinyl, or C₃-C₈ cycloalkyl, each    of which is unsubstituted or substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CN, CO₂H, heteroaryl selected from pyridyl, pyrimidyl,    pyrazinyl, (iso)quinolinyl, indolyl, thienyl, furanyl, pyrrolyl,    triazinyl, 1H-indazolyl, and benzimidazolyl, heterocycloalkyl    selected from piperidinyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydroisoquinolinyl, imidazolidinyl, piperazinyl, morpholinyl,    and S,S-dioxomorpholinyl, phenyl, naphthyl, wherein the heteroaryl,    heterocycloalkyl, phenyl and naphthyl groups are optionally    substituted with 1 or more groups that are independently selected    from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, OH, CF₃, and OCF₃,    C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄    alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl,        quinolinyl, pyrimidyl, furanyl, indolyl, benzofuranyl, thienyl,        cycloalkyl, wherein the cyclic portions are optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy;        wherein the heterocycloalkyl and the cycloalkyl portions of R₁        and R₁₀ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Other preferred compounds of Embodiment 1 include those where

-   X is —C(O)R₂₀;-   R₂₀ is NR₄R₅; wherein    -   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆        alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈        cycloalkyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl C₂-C₆ alkenyl,        cycloalkyl C₂-C₆ alkynyl, piperidinyl, pyrrolidinyl,        imidazolidinyl, morpholinyl, thiomorpholinyl,        S,S-dioxothiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl,        morpholinyl C₁-C₆ alkyl, thiomorpholinyl C₁-C₆ alkyl,        S,S-dioxothiomorpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl,        pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl,        piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,        imidazolidinyl C₂-C₆ alkenyl, morpholinyl C₂-C₆ alkenyl,        thiomorpholinyl C₂-C₆ alkenyl, S,S-dioxothiomorpholinyl C₂-C₆        alkenyl, tetrahydrofuranyl C₂-C₆ alkenyl, tetrahydrothienyl        C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl C₂-C₆        alkynyl, imidazolidinyl C₂-C₆ alkynyl, morpholinyl C₂-C₆        alkynyl, thiomorpholinyl C₂-C₆ alkynyl, S,S-dioxothiomorpholinyl        C₂-C₆ alkynyl, tetrahydrofuranyl C₂-C₆ alkynyl,        tetrahydrothienyl C₂-C₆ alkynyl, phenyl, naphthyl, furanyl,        pyridyl, pyrimidyl, pyrazinyl, thienyl, imidazolyl, pyrazinyl        C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, pyrimidyl C₁-C₆ alkyl,        pyrazinyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆        alkyl, thienyl C₁-C₆ alkyl, heteroarylalkenyl,        heteroarylalkynyl, phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl,        phenyl C₂-C₆ alkenyl, naphthyl C₂-C₆ alkenyl, phenyl C₂-C₆        alkynyl, naphthyl C₂-C₆ alkynyl, wherein the cyclic portion of        each of the above is unsubstituted or substituted with one or        more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,        halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,        NO₂, CN, OH, phenyl C₁-C₆ alkyl wherein the phenyl is optionally        substituted with 1, 2, 3, 4, or 5 groups that are independently        selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and        alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆        alkanoyl, NR₇R₈, or —C(O)NR₇R₈,        -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl,            wherein the C₁-C₆ alkyl is optionally substituted with 1, 2,            or 3 groups that are independently C₁-C₆ alkoxycarbonyl,            halogen, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl),            N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H;        -   wherein the heterocycloalkyl and the cycloalkyl portions of            R₄ and R₅ are further optionally substituted with ═O, ═N—OH,            or ═N—OCH₃; or    -   R₄ and R₅ and the nitrogen to which they are attached form a        piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl,        thiomorpholinyl, imidazolidinyl, S,S,-dioxothiomorpholinyl,        piperidinyl, pyrrolidinyl, ring, which is unsubstituted or        substituted with 1 or more groups that are independently C₁-C₆        alkyl, C₁-C₆ alkoxy, halogen, phenyl C₁-C₆ alkyl, naphthyl C₁-C₆        alkyl, C₁-C₆ alkanoyl, OH, ═O, pyridyl, pyrimidyl, pyrazinyl,        pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, phenyl, naphthyl,        —OCH₂CH₂O—, —OCH₂O—,        -   wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆            alkyl, phenyl and naphthyl groups are unsubstituted or            substituted with 1 or more groups that are independently            C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.

Other preferred compounds of Embodiment 1 include those of embodiment 4,i.e., compounds of Embodiment 1 where

-   R₁ is halogen, C₁-C₆ alkanoyl, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆    alkenyl, phenyl, naphthyl, thienyl, furanyl, indolyl, pyridyl,    pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl,    isoxazolyl, benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl,    piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl,    thiomorpholinyl, S,S-dioxothiomorpholinyl, or C₃-C₈ cycloalkyl, each    of which is unsubstituted or substituted with 1, 2, 3, 4, or 5    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CN, CO₂H, heteroaryl selected from pyridyl, pyrimidyl,    pyrazinyl, (iso)quinolinyl, indolyl, thienyl, furanyl, pyrrolyl,    triazinyl, 1H-indazolyl, and benzimidazolyl, heterocycloalkyl    selected from piperidinyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydroisoquinolinyl, imidazolidinyl, piperazinyl, morpholinyl,    and S,S-dioxomorpholinyl, phenyl, naphthyl, wherein the heteroaryl,    heterocycloalkyl, phenyl and naphthyl groups are optionally    substituted with 1 or more groups that are independently selected    from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, OH, CF₃, and OCF₃,    C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)    —NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl,        quinolinyl, pyrimidyl, furanyl, indolyl, C₃-C₈ cycloalkyl,        wherein the cyclic portions are optionally substituted with        halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄        haloalkyl, or C₁-C₄ haloalkoxy;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₁        and R₁₀ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃; and-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈    cycloalkyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl C₂-C₆ alkenyl, cycloalkyl    C₂-C₆ alkynyl, piperidinyl, pyrrolidinyl, imidazolidinyl,    morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl,    tetrahydrofuranyl, tetrahydrothienyl, morpholinyl C₁-C₆ alkyl,    thiomorpholinyl C₁-C₆ alkyl, S,S-dioxothiomorpholinyl C₁-C₆ alkyl,    piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl    C₁-C₆ alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    imidazolidinyl C₂-C₆ alkenyl, morpholinyl C₂-C₆ alkenyl,    thiomorpholinyl C₂-C₆ alkenyl, S,S-dioxothiomorpholinyl C₂-C₆    alkenyl, tetrahydrofuranyl C₂-C₆ alkenyl, tetrahydrothienyl C₂-C₆    alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl C₂-C₆ alkynyl,    imidazolidinyl C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl,    thiomorpholinyl C₂-C₆ alkynyl, S,S-dioxothiomorpholinyl C₂-C₆    alkynyl, tetrahydrofuranyl C₂-C₆ alkynyl, tetrahydrothienyl C₂-C₆    alkynyl, phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl,    thienyl, imidazolyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl,    pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, imidazolyl C₁-C₆    alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, heteroarylalkenyl,    heteroarylalkynyl, phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, phenyl    C₂-C₆ alkenyl, naphthyl C₂-C₆ alkenyl, phenyl C₂-C₆ alkynyl,    naphthyl C₂-C₆ alkynyl, wherein the cyclic portion of each of the    above is unsubstituted or substituted with one or more groups that    are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of the        above are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃; or-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,    imidazolidinyl, S,S,-dioxothiomorpholinyl, piperidinyl,    pyrrolidinyl, ring, which is unsubstituted or substituted with 1 or    more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl,    OH, ═O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl,    pyrazinyl C₁-C₆ alkyl, phenyl, naphthyl, —OCH₂CH₂O—, —OCH₂O—,    -   wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆        alkyl, phenyl and naphthyl groups are unsubstituted or        substituted with 1 or more groups that are independently C₁-C₄        alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.

Preferred compounds of Embodiment 4 include those of embodiment 5, i.e.,compounds of Embodiment 4 where R₂ and R₃ are independently H, halogen,or C₁-C₆ alkyl. In another aspect, R₂ and R₃ are independently H orC₁-C₄ alkyl.

Other preferred compounds of Embodiment 5 include those of embodiment 6,i.e., compounds of Embodiment 5 where Z is a bond, —CH₂—, or —NH—.

Other preferred compounds of Embodiment 6 include those of embodiment 7,i.e., compounds of Embodiment 6 where

-   R₁ is halogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, phenyl, thienyl, pyridyl,    triazolyl, imidazolyl, pyrazinyl, benzofuranyl,    3,4-dihydropyrimidin-2(1H)-onyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, heteroaryl    selected from pyridyl, pyrimidyl, pyrazinyl, indolyl, thienyl,    furanyl, pyrrolyl, and benzimidazolyl, heterocycloalkyl selected    from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, and    S,S-dioxomorpholinyl, phenyl, or naphthyl, wherein the heteroaryl,    heterocycloalkyl, phenyl and naphthyl groups are optionally    substituted with 1 or more groups that are independently selected    from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, OH, CF₃, and OCF₃,    C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O) R₁₀, or, NR₆R₇, —(C₁-C₄ alkyl)    —NR₆R₇, —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N (C₁-C₆ alkyl) (C₁-C₆        alkyl); and    -   R₁₀ is phenyl, pyridyl, or C₃-C₈ cycloalkyl, wherein the cyclic        portions are optionally substituted with halogen, C₁-C₆ alkyl,        C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄        haloalkoxy.

Other preferred compounds of Embodiment 7 include those of Embodiment 8,i.e., compounds of Embodiment 7 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,    morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆    alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl, furanyl, pyridyl,    pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl,    furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl    C₂-C₆ alkenyl, phenyl C₂-C₆ alkynyl, wherein the cyclic portion of    each of the above is unsubstituted or substituted with one or more    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH,    phenyl C₁-C₆ alkyl wherein the phenyl is optionally substituted with    1, 2, 3, 4, or 5 groups that are independently selected from C₁-C₄    alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy    C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or    —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl,        -   wherein the C₁-C₆ alkyl is optionally substituted with 1, 2,            or 3 groups that are independently C₁-C₆ alkoxycarbonyl,            halogen, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl),            N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Other preferred compounds of Embodiment 8 include those of Embodiment 9,i.e., compounds of Embodiment 8 where

-   Z is —NH— or —CH₂—;-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, phenyl, thienyl, pyridyl,    triazolyl, imidazolyl, pyrazinyl, benzofuranyl,    3,4-dihydropyrimidin-2(1H)-onyl, each of which is unsubstituted or    substituted with 1, 2, 3, 4, or 5 groups that are independently    C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, heteroaryl    selected from pyridyl, pyrimidyl, indolyl, thienyl, furanyl, and    benzimidazolyl, heterocycloalkyl selected from piperidinyl,    pyrrolidinyl, piperazinyl, morpholinyl, and S,S-dioxomorpholinyl,    phenyl, naphthyl, wherein the heteroaryl, heterocycloalkyl, phenyl    and naphthyl groups are optionally substituted with phenyl, wherein    the phenyl is optionally substituted with 1 or more groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,    OH, CF₃, and OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, C₁-C₆ alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or    —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); and    -   and-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,    morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆    alkyl, phenyl, furanyl, pyridyl, pyrazinyl C₁-C₆ alkyl, pyridyl    C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₄ alkyl, thienyl    C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, wherein the cyclic portion of each    of the above is unsubstituted or substituted with one or more groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    —SO₂—(C₁-C₆) alkyl, CF₃, OCF₃, NO₂, CN, OH, phenyl C₁-C₆ alkyl    wherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5    groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;        wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Other preferred compounds of Embodiment 9 include those of Embodiment10, i.e., compounds of Embodiment 9 where

-   R₁ is phenyl, thienyl, pyridyl, imidazolyl, pyrazinyl, benzofuranyl,    each of which is unsubstituted or substituted with 1, 2, or 3 groups    that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN,    CO₂H, pyridyl, piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl    or phenyl, wherein the pyridyl, pyrrolidinyl, morpholinyl, and    phenyl groups are optionally substituted with 1 or more groups that    are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,    OH, OH, CF₃, and OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, C₁-C₆ alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)—NR₆R₇, or    —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, or C₁-C₆        alkoxycarbonyl (in one aspect, tert-butylalkoxycarbonyl),        wherein the alkyl portion of each is unsubstituted or        substituted with 1, 2, or 3, groups that are independently        halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl)        (C₁-C₆ alkyl); and    -   and-   R₄ and R₅ are independently H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl,    piperidinyl, pyrrolidinyl, morpholinyl C₁-C₄ alkyl, piperidinyl    C₁-C₄ alkyl, phenyl, furanyl, pyridyl, pyrazinyl C₁-C₄ alkyl,    pyridyl C₁-C₄ alkyl, imidazolyl C₁-C₄ alkyl, furanyl C₁-C₄ alkyl,    thienyl C₁-C₄ alkyl, phenyl C₁-C₄ alkyl, wherein the cyclic portion    of each of the above is unsubstituted or substituted with one or    more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, —SO₂—(C₁-C₄) alkyl, CF₃, OCF₃, NO₂, CN, OH, NR₇R₈, or    —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, or 2 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;        wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Other preferred compounds of Embodiment 10 include those of Embodiment11, i.e., compounds of Embodiment 10 where

-   R₄ is H or methyl; and-   R₅ is —CH₂-furanyl.

Other preferred compounds of Embodiment 11 include those of Embodiment12, i.e., compounds of Embodiment 11 where

-   R₁ is phenyl, thienyl, pyridyl, or pyrazinyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CF₃, OCF₃,    NR₆R₇, —(C₁-C₂ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ at each occurrence are independently H, C₁-C₆        alkyl, or C₁-C₄ alkoxycarbonyl.

Other preferred compounds of Embodiment 12 include those of Embodiment12A, i.e., compounds of Embodiment 12 where

-   R₁ is phenyl, which is unsubstituted or substituted with 1, 2, or 3    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CF₃, OCF₃, NR₆R₇, —(C₁-C₂ alkyl)—NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl,        or C₁-C₄ alkoxycarbonyl. In another aspect, R₆ and R₇ are        independently H or C₁-C₄ alkyl.

Other preferred compounds of Embodiment 12 include those of Embodiment12B, i.e., compounds of Embodiment 12 where

-   R₁ is thienyl, which is unsubstituted or substituted with 1, 2, or 3    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CF₃, OCF₃, NR₆R₇, —(C₁-C₂ alkyl)—NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl,        or C₁-C₄ alkoxycarbonyl. In another aspect, R₆ and R₇ are        independently H or C₁-C₄ alkyl.

Other preferred compounds of Embodiment 12 include those of Embodiment12C, i.e., compounds of Embodiment 12 where

-   R₁ is pyridyl, which is unsubstituted or substituted with 1, 2, or 3    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CF₃, OCF₃, NR₆R₇, —(C₁-C₂ alkyl)—NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl,        or C₁-C₄ alkoxycarbonyl. In another aspect, R₆ and R₇ are        independently H or C₁-C₄ alkyl.

Other preferred compounds of Embodiment 12 include those of Embodiment12D, i.e., compounds of Embodiment 12 where

-   R₁ is pyrazinyl, which is unsubstituted or substituted with 1, 2, or    3 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, CF₃, OCF₃, NR₆R₇, —(C₁-C₂ alkyl)—NR₆R₇, or —C(O)NR₆R₇, wherein    -   R₆ and R₇ at each occurrence are independently H, C₁-C₆ alkyl,        or C₁-C₄ alkoxycarbonyl. In another aspect, R₆ and R₇ are        independently H or C₁-C₄ alkyl.

Other preferred compounds of the invention are within Embodiment 12E,i.e., compounds of embodiments 12, 12A, 12B, 12C, and 12D, wherein atleast one of R₂ and R₃ is H. In another aspect, both R₂ and R₃ are H.

More preferred compounds of the invention include those of Embodiment12F, i.e., compounds according to embodiment 12E wherein R₄ is H.

Still other preferred compounds of Embodiment 6 include those ofembodiment 13, i.e., compounds of Embodiment 6 where R₄ and R₅ and thenitrogen to which they are attached form a piperazinyl, morpholinyl,piperidinyl, imidazolidinyl, or pyrrolidinyl ring, each of which isunsubstituted or substituted with 1 or more groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₄ alkyl,C₁-C₆ alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄alkyl, pyrazinyl C₁-C₄ alkyl, phenyl, —OCH₂CH₂O—, —OCH₂O—,

wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl, andphenyl groups are unsubstituted or substituted with 1 or more groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.

Still other preferred compounds of Embodiment 13 include those ofembodiment 14, i.e., compounds of Embodiment 13 where

-   R₁ is phenyl, thienyl, furanyl, pyridyl, pyrimidyl, pyrazinyl,    triazolyl, imidazolyl, oxazolyl, benzofuranyl, each of which is    unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl, indolyl,    thienyl, furanyl, pyrrolyl, and benzimidazolyl, heterocycloalkyl    selected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl,    and S,S-dioxomorpholinyl, phenyl, or naphthyl, wherein the    heteroaryl, heterocycloalkyl, phenyl and naphthyl groups are    optionally substituted with 1 or more groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, OH, CF₃, and    OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₄ alkyl, C₁-C₄ alkoxycarbonyl, or C₁-C₄    alkanoyl.

Still other preferred compounds of Embodiment 13 include those ofembodiment 15, i.e., compounds of Embodiment 13 where

-   R₁ is phenyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, triazolyl,    imidazolyl, or benzofuranyl, each of which is unsubstituted or    substituted with 1, 2, or 3 groups that are independently C₁-C₆    alkyl, halogen, C₁-C₆ alkoxy, OH, —C(O)R₁₀, NR₆R₇, —(C₁-C₄    alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, or 2 groups that        are independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl)        or N(C₁-C₆ alkyl) (C₁-C₆ alkyl);    -   R₁₀ is phenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl,        furanyl, indolyl, or C₃-C₈ cycloalkyl, each of which is        optionally substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,        OH, CO₂H, CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₁        and R₁₀ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Embodiment 16 includes compounds of Embodiments 14 and 15 wherein

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, imidazolidinyl, or    pyrrolidinyl ring, each of which is unsubstituted or substituted    with 1 or more groups that are independently C₁-C₄ alkyl, C₁-C₄    alkoxy, halogen, phenyl C₁-C₂ alkyl, C₁-C₆ alkanoyl, OH, pyridyl,    pyrimidyl C₁-C₂ alkyl, phenyl, —OCH₂CH₂O—, or —OCH₂O—; and-   R₂ and R₃ are both H.

Other preferred compounds of Embodiment 16 include those of embodiment16A, i.e., compounds of Embodiment 16 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring, each of    which is substituted with 1 or more groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₂ alkyl, C₁-C₆    alkanoyl, OH, pyridyl, pyrimidyl C₁-C₂ alkyl, phenyl, —OCH₂CH₂O—, or    —OCH₂O—.

Embodiment 16B includes compounds of embodiments 16 and 16A wherein

-   R₁ is phenyl, which is unsubstituted or substituted with 1, 2, or 3    groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,    OH, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆        alkyl) (C₁-C₆ alkyl); and    -   R₁₀ is phenyl, pyridyl, or furanyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃, or OCF₃.

Embodiment 16C includes compounds of embodiments 16 and 16A wherein

-   R₁ is thienyl, triazolyl, imidazolyl, or benzofuranyl, each of which    is unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆        alkyl) (C₁-C₆ alkyl); and    -   R₁₀ is phenyl, pyridyl, or furanyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃, or OCF₃.

Embodiment 16D includes compounds of embodiments 16 and 16A wherein

-   R₁ is pyridyl, pyrimidyl, or pyrazinyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆        alkyl) (C₁-C₆ alkyl); and    -   R₁₀ is phenyl, pyridyl, or furanyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃, or OCF₃.

Embodiment 16E includes compounds of embodiments 16, 16A, 16B, 16C, and16D wherein Z is a bond.

Embodiment 16E includes compounds of embodiments 16, 16A, 16B, 16C, and16D wherein Z is —CH₂—.

Embodiment 16G includes compounds of embodiments 16, 16A, 16B, 16C, and16D wherein Z is —NH—.

Embodiment 16H includes compounds of embodiments 16, 16A, 16B, 16C, and16D wherein Z is —S— or —SO₂—.

Embodiment 16I includes compounds of embodiments 16, 16A, 16B, 16C, and16D wherein Z is —SO₂NH—, or —SO₂N(C₁-C₄ alkyl)-.

In still another aspect, the invention provides compounds according toembodiments 5, 16, and 16A-16I, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiments 5, 16, and 16A-16I, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiments 5, 16, and 16A-16I, wherein R₂₁ is amino, monoalkylamino,or dialkylamino.

In yet another aspect, the invention provides compounds of embodiments5, 16, and 16A-16I, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiments5, 16, and 16A-16I, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiments5, 16, and 16A-16I, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiments5, 16, and 16A-16I, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiments5, 16, and 16A-16I, wherein R₂₁ is phenyl, which is substituted with 1-5groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (inone aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 5, 16, and 16A-16I, wherein R₂₁ is pyridyl, or pyrimidyl,each of which is optionally substituted with 1-5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 5, 16, and 16A-16I, wherein R₂₁ is indolyl or(iso)quinolinyl, each of which is optionally substituted with 1-5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxylC₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in oneaspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiments5, 16, and 16A-16I, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, or C₂-C₆alkenyl.

In still yet another aspect, the invention provides compounds ofembodiments 5, 16, and 16A-16I, wherein R₂₁ is —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Still other preferred compounds of Embodiment 5 include those ofembodiment 17, i.e., compounds of Embodiment 5 where

-   R₁ is halogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of    which is unsubstituted or substituted with 1, 2, or 3 groups that    are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl, indolyl,    thienyl, furanyl, pyrrolyl, and benzimidazolyl, heterocycloalkyl    selected from piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl,    and S,S-dioxomorpholinyl, phenyl, or naphthyl, wherein the    heteroaryl, heterocycloalkyl, phenyl and naphthyl groups are    optionally substituted with 1 or more groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, OH, CF₃, and    OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇,    wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl,        quinolinyl, pyrimidyl, furanyl, indolyl, C₃-C₈ cycloalkyl,        wherein the cyclic portions are optionally substituted with        halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄        haloalkyl, or C₁-C₄ haloalkoxy;    -   wherein the cycloalkyl portion of R₁₀ is further optionally        substituted with ═O, ═N-OH, or ═N—OCH₃.

Other preferred compounds of Embodiment 17 include those of embodiment18, i.e., compounds of Embodiment 17 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,    imidazolidinyl, S,S,-dioxothiomorpholinyl, piperidinyl,    pyrrolidinyl, ring, which is unsubstituted or substituted with 1 or    more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl,    OH, ═O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl,    pyrazinyl C₁-C₆ alkyl, phenyl, naphthyl, —OCH₂CH₂O—, or —OCH₂O—,    -   wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆        alkyl, phenyl and naphthyl groups are unsubstituted or        substituted with 1 or more groups that are independently C₁-C₄        alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.

Other preferred compounds of Embodiment 18 include those of embodiment19, i.e., compounds of Embodiment 18 where R₁ is halogen.

Other preferred compounds of Embodiment 18 include those of embodiment20, i.e., compounds of Embodiment 18 where

-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    pyrrolyl, piperidinyl, pyrrolidinyl, piperazinyl morpholinyl, or    phenyl,    -   wherein the cyclic groups are optionally substituted with 1 or        more groups that are independently selected from C₁-C₄ alkyl,        C₁-C₄ alkoxy, halogen, OH, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is phenyl or pyridyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃ or OCF₃.

Other preferred compounds of Embodiment 20 include those of embodiment21, i.e., compounds of Embodiment 20 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, piperidinyl, or pyrrolidinyl    ring, each of which is unsubstituted or substituted with 1 or more    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, OH, ═O,    pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl    C₁-C₆ alkyl, phenyl, naphthyl, —OCH₂CH₂O—, or —OCH₂O—.

Other preferred compounds of Embodiment 21 include those of embodiment22, i.e., compounds of Embodiment 21 where

-   R₁ is C₂-C₆ alkynyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Other preferred compounds of Embodiment 21 include those of embodiment23, i.e., compounds of Embodiment 21 where

-   R₁ is C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Other preferred compounds of Embodiment 21 include those of embodiment24, i.e., compounds of Embodiment 21 where

-   R₁ is C₁-C₆ alkenyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Embodiment 24A includes compounds of embodiments 19, 20, 21, 22, 23, and24, wherein Z is a bond.

Embodiment 24B includes compounds of embodiments 20, 21, 22, 23, and 24,wherein Z is —CH₂—.

Embodiment 24C includes compounds of embodiments 20, 21, 22, 23, and 24,wherein Z is —NH—.

Embodiment 24D includes compounds of embodiments 20, 21, 22, 23, and 24,wherein Z is —S— or —SO₂—.

Embodiment 24E includes compounds of embodiments 20, 21, 22, 23, and 24,wherein Z is —N(C₁-C₄ alkyl)-. In another aspect, Z is —N(C₁-C₂ alkyl)-.In still another aspect, Z is —N(C₂-C₃ alkyl)-.

Embodiment 24F includes compounds of embodiments 20, 21, 22, 23, and 24,wherein Z is —SO₂NH—, or —SO₂N(C₁-C₄ alkyl)-.

In still another aspect, the invention provides compounds according toembodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is amino,monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of embodiments20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiments20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiments20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiments20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiments20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is phenyl, which issubstituted with 1-5 groups that are independently C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect,CF₃), or haloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is pyridyl, orpyrimidyl, each of which is optionally substituted with 1-5 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is indolyl or(iso)quinolinyl, each of which is optionally substituted with 1-5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxylC₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in oneaspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiments20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆alkynyl, or C₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds ofembodiments 20, 21, 22, 23, 24, and 24A-24F, wherein R₂₁ is —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Still other preferred compounds of Embodiment 17 include those ofEmbodiment 25, i.e., compounds of Embodiment 17 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,    morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆    alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl, furanyl, pyridyl,    pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl,    furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl    C₂-C₆ alkenyl, phenyl C₂-C₆ alkynyl, wherein the cyclic portion of    each of the above is unsubstituted or substituted with one or more    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH,    phenyl C₁-C₆ alkyl wherein the phenyl is optionally substituted with    1, 2, 3, 4, or 5 groups that are independently selected from C₁-C₄    alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy    C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or    —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Still other preferred compounds of Embodiment 25 include those ofEmbodiment 26, i.e., compounds of Embodiment 25 where

-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the pyridyl, piperidinyl and phenyl groups are        optionally substituted with 1 or more groups that are        independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,        OH, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is phenyl or pyridyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃ or OCF₃.

Still other preferred compounds of Embodiment 26 include those ofEmbodiment 27, i.e., compounds of Embodiment 26 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl C₁-C₆    alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, phenyl,    furanyl, pyridyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl,    imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl,    phenyl C₁-C₆ alkyl, wherein the cyclic portion of each of the above    is unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Still other preferred compounds of Embodiment 27 include those ofEmbodiment 28, i.e., compounds of Embodiment 27 where

-   R₁ is C₂-C₆ alkynyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Still other preferred compounds of Embodiment 27 include those ofEmbodiment 29, i.e., compounds of Embodiment 27 where

-   R₁ is C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Still other preferred compounds of Embodiment 27 include those ofEmbodiment 30, i.e., compounds of Embodiment 27 where

-   R₁ is C₁-C₆ alkenyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)—NR₆R₇, —C(O)NR₆R₇, piperidinyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Embodiment 30A includes compounds of embodiments 27, 28, and 29, whereinR₂ and R₃ are independently H or methyl. In another aspect, at least oneof R₂ and R₃ is H.

Preferred compounds of Embodiment 30A include those of Embodiment 30B,i.e., compounds of Embodiment 30A where wherein R₄ is H, C₁-C₆ alkyl, orC₁-C₄ alkoxy C₁-C₆ alkyl.

Preferred compounds of Embodiment 30B include those of Embodiment 30C,i.e., compounds of Embodiment 30B where

-   R₅ is piperidinyl, pyrrolidinyl, morpholinyl, phenyl, furanyl, or    pyridyl, wherein the cyclic portion of each of the above is    unsubstituted or substituted with one or more groups that are    independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, CF₃, OCF₃, NO₂, CN, OH, phenyl C₁-C₄ alkyl wherein the phenyl    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen,    OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,    C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl,        -   wherein the C₁-C₆ alkyl is optionally substituted with 1, 2,            or 3 groups that are independently C₁-C₆ alkoxycarbonyl,            halogen, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl),            N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 30B include those of Embodiment 30D,i.e., compounds of Embodiment 30B where

-   R₅ is morpholinyl C₁-C₄ alkyl, piperidinyl C₁-C₄ alkyl, pyrrolidinyl    C₁-C₄ alkyl, pyrazinyl C₁-C₄ alkyl, pyridyl C₁-C₄ alkyl, imidazolyl    C₁-C₄ alkyl, furanyl C₁-C₄ alkyl, thienyl C₁-C₄ alkyl, or phenyl    C₁-C₄ alkyl, wherein the cyclic portion of each of the above is    unsubstituted or substituted with one or more groups that are    independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, CF₃, OCF₃, NO₂, CN, OH, phenyl C₁-C₄ alkyl wherein the phenyl    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen,    OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,    C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Embodiment 30E includes compounds of embodiments 30C and 30D, wherein Zis a bond.

Embodiment 30F includes compounds of embodiments 30C and 30D, wherein Zis —CH₂—.

Embodiment 30G includes compounds of embodiments 30C and 30D, wherein Zis —NH—.

Embodiment 30H includes compounds of embodiments 30C and 30D, wherein Zis —S— or —SO₂—.

Embodiment 30I includes compounds of embodiments 30C and 30D, wherein Zis —N(C₁-C₄ alkyl)-. In another aspect, Z is —N(C₁-C₂ alkyl)-. In stillanother aspect, Z is —N(C₂-C₃ alkyl)-.

30J. A compound according to either embodiment 30C or 30D, wherein Z is—SO₂NH—, or —SO₂N(C₁-C₄ alkyl)-.

In still another aspect, the invention provides compounds according toembodiments 27, 28, 29, 30, and 30A-30I, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiments 27, 28, 29, 30, and 30A-30I, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiments 27, 28, 29, 30, and 30A-30I, wherein R₂₁ is amino,monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of embodiments27, 28, 29, 30, and 30A-30I, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiments27, 28, 29, 30, and 30A-30I, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiments27, 28, 29, 30, and 30A-30I, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiments27, 28, 29, 30, and 30A-30I, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiments27, 28, 29, 30, and 30A-30I, wherein R₂₁ is phenyl, which is substitutedwith 1-5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), orhaloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 27, 28, 29, 30, and 30A-30I, wherein R₂₁ is pyridyl orpyrimidyl, each of which is optionally substituted with 1-5 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 27, 28, 29, 30, and 30A-30I, wherein R₂₁ is indolyl or(iso)quinolinyl, each of which is optionally substituted with 1-5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxylC₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in oneaspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiments27, 28, 29, 30, and 30A-30I, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl,or C₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds ofembodiments 27, 28, 29, 30, and 30A-30I, wherein R₂₁ is —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Other preferred compounds of Embodiment 17 include those of Embodiment31, i.e., compounds of Embodiment 17 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl,    wherein the cycloalkyl is unsubstituted or substituted with one or    more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂,    CN, OH, phenyl C₁-C₆ alkyl wherein the phenyl is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and    alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;        wherein the cycloalkyl portion of R₄ and R₅ is further        optionally substituted with ═O, ═N—OH, or ═N—OCH₃.

Other preferred compounds of Embodiment 31 include those of Embodiment32, i.e., compounds of Embodiment 31 where

-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is phenyl or pyridyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃ or OCF₃.

Other preferred compounds of Embodiment 31 include those of Embodiment33, i.e., compounds of Embodiment 31 where

-   R₁ is C₂-C₆ alkynyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Other preferred compounds of Embodiment 31 include those of Embodiment34, i.e., compounds of Embodiment 31 where

-   R₁ is C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Other preferred compounds of Embodiment 31 include those of Embodiment35, i.e., compounds of Embodiment 31 where

-   R₁ is C₁-C₆ alkenyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Other preferred compounds of Embodiment 31 include those of Embodiment35A, i.e., compounds of Embodiment 31 where R₁ is halogen.

Embodiment 35B includes compounds of embodiments 33, 34, and 35, whereinR₄ is H, C₁-C₆ alkyl, or C₁-C₄ alkoxy C₁-C₆ alkyl.

Other preferred compounds of Embodiment 35B include those of Embodiment35C, i.e., compounds of Embodiment 35B where

-   R₅ is C₃-C₆ cycloalkyl, wherein the cycloalkyl is unsubstituted or    substituted with 1, 2, or 3 groups that are independently C₁-C₄    alkyl, C₁-C₄ alkoxy, halogen, —SO₂—(C₁-C₄) alkyl, CF₃, OCF₃, NO₂,    CN, OH, phenyl C₁-C₄ alkyl wherein the phenyl is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and    alkanoyl, C₁-C₄ alkoxy C₁-C₄ alkyl, C₁-C₄ alkoxycarbonyl, C₁-C₄    alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;        wherein the cycloalkyl portion of R₄ and R₅ is further        optionally substituted with ═O, ═N—OH, or ═N—OCH₃; and at least        one of R₂ and R₃ is H.

Other preferred compounds of Embodiment 35C include those of Embodiment35D, i.e., compounds of Embodiment 35C where wherein Z is a bond.

Other preferred compounds of Embodiment 35C include those of Embodiment35E, wherein Z is —CH₂—.

Other preferred compounds of Embodiment 35C include those of Embodiment35F wherein Z is —NH—.

Other preferred compounds of Embodiment 35C include those of Embodiment35G wherein Z is —S— or —SO₂—.

Other preferred compounds of Embodiment 35C include those of Embodiment35H wherein Z is —N(C₁-C₄ alkyl)-. In another aspect, Z is —N(C₁-C₂alkyl)-. In still another aspect, Z is —N(C₂-C₃ alkyl)-.

Other preferred compounds of Embodiment 35C include those of Embodiment35I wherein Z is —SO₂NH—, or —SO₂N(C₁-C₄ alkyl)-.

In still another aspect, the invention provides compounds according toembodiments 33, 34, 35, and 35A-35I, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiments 33, 34, 35, and 35A-35I, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingembodiments 33, 34, 35, and 35A-35I, wherein R₂₁ is amino,monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of embodiments33, 34, 35, and 35A-35I, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiments33, 34, 35, and 35A-35I, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiments33, 34, 35, and 35A-35I, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiments33, 34, 35, and 35A-35I, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiments33, 34, 35, and 35A-35I, wherein R₂₁ is phenyl, which is substitutedwith 1-5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), orhaloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 33, 34, 35, and 35A-35I, wherein R₂₁ is pyridyl orpyrimidyl, each of which is optionally substituted with 1-5 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 33, 34, 35, and 35A-35I, wherein R₂₁ is indolyl or(iso)quinolinyl, each of which is optionally substituted with 1-5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxylC₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in oneaspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiments33, 34, 35, and 35A-35I, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, orC₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds ofembodiments 33, 34, 35, and 35A-35I, wherein R₂₁ is —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Other preferred compounds of Embodiment 5 include those of Embodiment36, i.e., compounds of Embodiment 5 where

-   Z is a bond;-   R₁ is phenyl, naphthyl, thienyl, furanyl, indolyl, pyridyl,    pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl,    benzofuranyl, piperidinyl, pyrrolidinyl, piperazinyl, or    morpholinyl, each of which is unsubstituted or substituted with 1,    2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl, halogen,    C₁-C₆ alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, heteroaryl selected from    pyridyl, pyrimidyl, pyrazinyl, (iso)quinolinyl, indolyl, thienyl,    furanyl, pyrrolyl, triazinyl, 1H-indazolyl, and benzimidazolyl,    heterocycloalkyl selected from piperidinyl, pyrrolidinyl,    tetrahydrofuranyl, tetrahydroisoquinolinyl, imidazolidinyl,    piperazinyl, morpholinyl, and S,S-dioxomorpholinyl, phenyl,    naphthyl, wherein the heteroaryl, heterocycloalkyl, or phenyl, which    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃,    and OCF₃, wherein each R₆ and R₇ is independently H, C₁-C₆ alkyl,    C₁-C₄ alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion    of each is unsubstituted or substituted with 1, 2, or 3, groups that    are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); and-   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl,    quinolinyl, pyrimidyl, furanyl, indolyl, C₃-C₈ cycloalkyl, wherein    the cyclic portions are optionally substituted with halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄    haloalkoxy;    wherein the heterocycloalkyl and the cycloalkyl portions of R₁ and    R₁₀ are further optionally substituted with ═O, ═N—OH, or ═N—OCH₃.

Other preferred compounds of Embodiment 36 include those of Embodiment37, i.e., compounds of Embodiment 36 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, imidazolidinyl, or    pyrrolidinyl ring, each of which is unsubstituted or substituted    with 1 or more groups that are independently C₁-C₄ alkyl, C₁-C₄    alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆ alkanoyl, OH, pyridyl,    pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl, pyrazinyl C₁-C₄ alkyl,    phenyl, —OCH₂CH₂O—, —OCH₂O—,    wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl,    and phenyl groups are unsubstituted or substituted with 1 or more    groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,    CF₃ or OCF₃.

Other preferred compounds of Embodiment 37 include those of Embodiment38, i.e., compounds of Embodiment 37 where

-   R₁ is phenyl which is unsubstituted or substituted with 1, 2, 3, 4,    or 5 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆    alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)—NR₆R₇, —C(O)NR₆R₇, heteroaryl selected from    pyridyl, pyrimidyl, indolyl, thienyl, furanyl, and pyrrolyl,    heterocycloalkyl selected from piperidinyl, pyrrolidinyl,    piperazinyl, and morpholinyl, phenyl, wherein the heteroaryl,    heterocycloalkyl phenyl and naphthyl groups are optionally    substituted with each of which is optionally substituted with 1, 2,    3, 4, or 5 groups that are independently selected from C₁-C₄ alkyl,    C₁-C₄ alkoxy, halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆        alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Other preferred compounds of Embodiment 38 include those of Embodiment39, i.e., compounds of Embodiment 38 where

-   R₂ and R₃ are both H; and-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring, each of    which is substituted with 1 or more groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆    alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl,    pyrazinyl C₁-C₄ alkyl, phenyl, —OCH₂CH₂O—, or —OCH₂O—.

Preferred compounds of Embodiment 39 include those of Embodiment 39A,i.e., compounds of Embodiment 39 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring, wherein    the piperazinyl and piperidinyl rings are substituted at position 4,    wherein the morpholinyl, and pyrrolidinyl rings are substituted at    position 3.

Preferred compounds of Embodiment 37 include those of Embodiment 40,i.e., compounds of Embodiment 37 where

-   R₁ is thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl,    pyrazinyl, triazolyl, imidazolyl, benzofuranyl, piperidinyl,    pyrrolidinyl, piperazinyl, or morpholinyl, each of which is    unsubstituted or substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl)—NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, wherein the pyridyl, piperidinyl, and phenyl groups are    optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃,    and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); and        wherein the heterocycloalkyl portion of R₁₀ is further        optionally substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 40 include those of Embodiment 41,i.e., compounds of Embodiment 40 where

-   R₂ and R₃ are both H; and-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring, each of    which is substituted with 1 or more groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆    alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl,    pyrazinyl C₁-C₄ alkyl, phenyl, —OCH₂CH₂O—, or —OCH₂O—.

Preferred compounds of Embodiment 41 include those of Embodiment 42,i.e., compounds of Embodiment 41 where

-   R₁ is thienyl optionally substituted with 1, 2, 3, or 4 groups that    are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 41 include those of Embodiment 43,i.e., compounds of Embodiment 41 where

-   R₁ is benzofuranyl optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN,    CO₂H, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)—NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl, which is optionally substituted with 1, 2,    3, 4, or 5 groups that are independently selected from C₁-C₄ alkyl,    C₁-C₄ alkoxy, halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 36 include those of Embodiment 44,i.e., compounds of Embodiment 36 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,    morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆    alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl, furanyl, pyridyl,    pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl,    furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl    C₂-C₆ alkenyl, phenyl C₂-C₆ alkynyl, wherein the cyclic portion of    each of the above is unsubstituted or substituted with one or more    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    —SO₂— (C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH,    phenyl C₁-C₆ alkyl wherein the phenyl is optionally substituted with    1, 2, 3, 4, or 5 groups that are independently selected from C₁-C₄    alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy    C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or    —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 44 include those of Embodiment 45,i.e., compounds of Embodiment 44 where

-   R₁ is phenyl which is unsubstituted or substituted with 1, 2, 3, 4,    or 5 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆    alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆        alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 45 include those of Embodiment 45A,i.e., compounds of Embodiment 45 where

-   A compound according to embodiment 36, wherein-   R₄ is H, C₁-C₆ alkyl, or C₁-C₄ alkoxy C₁-C₆ alkyl.

Preferred compounds of Embodiment 45A include those of Embodiment 45B,i.e., compounds of Embodiment 45A where

-   R₅ is C₃-C₈ cycloalkyl, which is unsubstituted or substituted with    one or more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂,    CN, OH, phenyl C₁-C₆ alkyl wherein the phenyl is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and    alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the cycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 45A include those of Embodiment 45C,i.e., compounds of Embodiment 45A where

-   R₅ is piperidinyl, pyrrolidinyl, morpholinyl, phenyl, furanyl, or    pyridyl, wherein the cyclic portion of each of the above is    unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 45A include those of Embodiment 45D,i.e., compounds of Embodiment 45A where

-   R₅ is morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl    C₁-C₆ alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, pyrazinyl C₁-C₆ alkyl,    pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl,    thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl C₂-C₆ alkenyl,    phenyl C₂-C₆ alkynyl, wherein the cyclic portion of each of the    above is unsubstituted or substituted with one or more groups that    are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 45A include those of Embodiment 45E,i.e., compounds of Embodiment 45A where

-   R₅ is morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl    C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl    C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, or phenyl    C₁-C₆ alkyl, wherein the cyclic portion of each of the above is    unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 45A include those of Embodiment 45F,i.e., compounds of Embodiment 45A where

-   R₅ is piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl C₂-C₆ alkenyl, or    phenyl C₂-C₆ alkynyl, wherein the cyclic portion of each of the    above is unsubstituted or substituted with one or more groups that    are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

In still another aspect, the invention provides compounds according toembodiments 45 and 45A-45F, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiments 45 and 45A-45F, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiments 45 and 45A-45F, wherein R₂₁ is amino, monoalkylamino, ordialkylamino.

In yet another aspect, the invention provides compounds of embodiments45 and 45A-45F, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiments45 and 45A-45F, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiments45 and 45A-45F, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiments45 and 45A-45F, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiments45 and 45A-45F, wherein R₂₁ is phenyl, which is substituted with 1-5groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (inone aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 45 and 45A-45F, wherein R₂₁ is pyridyl or pyrimidyl, each ofwhich is optionally substituted with 1-5 groups that are independentlyC₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl(in one aspect, CF₃), or haloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 45 and 45A-45F, wherein R₂₁ is indolyl or (iso)quinolinyl,each of which is optionally substituted with 1-5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In still another aspect, the invention provides compounds of embodiments45 or 45A-45F, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, or C₂-C₆alkenyl.

In still yet another aspect, the invention provides compounds ofembodiments 45 or 45A-45F, wherein R₂₁ is —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 36 include those of Embodiment 46,i.e., compounds of Embodiment 36 where

-   -   R₂ and R₃ are both H; and

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl C₁-C₆    alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, phenyl,    furanyl, pyridyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl,    imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl,    phenyl C₁-C₆ alkyl, wherein the cyclic portion of each of the above    is unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 46 include those of Embodiment 47,i.e., compounds of Embodiment 46 where

-   R₁ is thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl,    pyrazinyl, triazolyl, imidazolyl, benzofuranyl, piperidinyl,    pyrrolidinyl, piperazinyl, or morpholinyl, each of which is    unsubstituted or substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl).

Preferred compounds of Embodiment 47 include those of Embodiment 48,i.e., compounds of Embodiment 47 where

-   R₁ is thienyl optionally substituted with 1, 2, 3, or 4 groups that    are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 47 include those of Embodiment 49,i.e., compounds of Embodiment 47 where

-   R₁ is benzofuranyl optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN,    CO₂H, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, or phenyl, which    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃,    and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl).

Embodiment 49A includes compounds of embodiments 47, 48 and 49, wherein,R₄ is H, C₁-C₆ alkyl, or C₁-C₄ alkoxy C₁-C₆ alkyl.

Preferred compounds of Embodiment 49A include those of Embodiment 49B,i.e., compounds of Embodiment 49A where

-   R₅ is piperidinyl, pyrrolidinyl, morpholinyl, phenyl, furanyl, or    pyridyl, wherein the cyclic portion of each of the above is    unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, CF₃, OCF₃, NO₂, CN, OH, phenyl C₁-C₄ alkyl wherein the phenyl    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen,    OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,    C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₄ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 49A include those of Embodiment 49C,i.e., compounds of Embodiment 49A where

-   R₅ is morpholinyl C₁-C₄ alkyl, piperidinyl C₁-C₄ alkyl, pyrrolidinyl    C₁-C₄ alkyl, pyrazinyl C₁-C₄ alkyl, pyridyl C₁-C₄ alkyl, imidazolyl    C₁-C₄ alkyl, furanyl C₁-C₄ alkyl, thienyl C₁-C₄ alkyl, or phenyl    C₁-C₄ alkyl, wherein the cyclic portion of each of the above is    unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, CF₃, OCF₃, NO₂, CN, OH, phenyl C₁-C₆ alkyl wherein the phenyl    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen,    OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,    C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl portion of R₅ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

In still another aspect, the invention provides compounds according toembodiments 47, 48, 49, and 49A-49C, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiments 47, 48, 49, and 49A-49C, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiments 47, 48, 49, and 49A-49C, wherein R₂₁ is amino,monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of embodiments47, 48, 49, and 49A-49C, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiments47, 48, 49, and 49A-49C, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiments47, 48, 49, and 49A-49C, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiments47, 48, 49, and 49A-49C, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiments47, 48, 49, and 49A-49C, wherein R₂₁ is phenyl, which is substitutedwith 1-5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), orhaloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 47, 48, 49, and 49A-49C, wherein R₂₁ is pyridyl orpyrimidyl, each of which is optionally substituted with 1-5 groups thatare independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiments 47, 48, 49, and 49A-49C, wherein R₂₁ is indolyl or(iso)quinolinyl, each of which is optionally substituted with 1-5 groupsthat are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxylC₁-C₄ alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in oneaspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiments47, 48, 49, and 49A-49C, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, orC₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds ofembodiments 45 and 45A-45F, wherein R₂₁ is —C(O)NH₂, —C(O)NH(C₁-C₆alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 2 include those of Embodiment 50,i.e., compounds of Embodiment 2 where

-   X is —C(O)R₂₀, or —NR_(x)R_(y); wherein    -   R₂₀ is OH or C₁-C₆ alkoxy; and    -   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, phenyl C₁-C₄ alkoxycarbonyl, phenyl, naphthyl,        phenyl C₁-C₄ alkyl, —C(O)-phenyl, —C(O)-naphthyl, pyridyl,        pyrimidyl, pyrazinyl, benzofuranyl, indolyl, benzimidazolyl,        thienyl, furanyl, quinolinyl, isoquinolinyl, pyridyl C₁-C₆        alkyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl,        benzofuranyl C₁-C₆ alkyl, indolyl C₁-C₆ alkyl, benzimidazolyl        C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl,        quinolinyl C₁-C₆ alkyl, isoquinolinyl C₁-C₆ alkyl, or        —C(O)-pyridyl, —C(O)-pyrimidyl, —C(O) -pyrazinyl,        —C(O)-benzofuranyl, —C(O)-indolyl, —C(O)-benzimidazolyl,        —C(O)-thienyl, —C(O)-furanyl, —C(O)-quinolinyl, or        —C(O)-isoquinolinyl, wherein the ring portions of the above are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H, NR₆R₇,        —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, CF₃,        or OCF₃.

Preferred compounds of Embodiment 50 include those of Embodiment 51,i.e., compounds of Embodiment 50 where

-   R₁ is halogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of    which is unsubstituted or substituted with 1, 2, or 3 groups that    are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    heteroaryl selected from pyridyl, pyrimidyl, pyrazinyl,    (iso)quinolinyl, indolyl, thienyl, furanyl, pyrrolyl, triazinyl,    1H-indazolyl, and benzimidazolyl, heterocycloalkyl selected from    piperidinyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydroisoquinolinyl, imidazolidinyl, piperazinyl, morpholinyl,    and S,S-dioxomorpholinyl, phenyl, or naphthyl, wherein the    heteroaryl, heterocycloalkyl, phenyl and naphthyl groups are    optionally substituted with 1 or more groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, CF₃, and OCF₃,    CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl,        quinolinyl, pyrimidyl, furanyl, indolyl, C₃-C₈ cycloalkyl,        wherein the cyclic portions are optionally substituted with        halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄        haloalkyl, or C₁-C₄ haloalkoxy;    -   wherein the cycloalkyl portion of R₁₀ is further optionally        substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 51 include those of Embodiment 52,i.e., compounds of Embodiment 51 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl,    imidazolidinyl, S,S,-dioxothiomorpholinyl, piperidinyl,    pyrrolidinyl, ring, which is unsubstituted or substituted with 1 or    more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl,    OH, ═O, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl,    pyrazinyl C₁-C₆ alkyl, phenyl, naphthyl, —OCH₂CH₂O—, or —OCH₂O—,    -   wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆        alkyl, phenyl and naphthyl groups are unsubstituted or        substituted with 1 or more groups that are independently C₁-C₄        alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.

Preferred compounds of Embodiment 52 include those of Embodiment 53,i.e., compounds of Embodiment 52 where R₁ is halogen.

Preferred compounds of Embodiment 52 include those of Embodiment 54,i.e., compounds of Embodiment 52 where

-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is phenyl or pyridyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃ or OCF₃.

Preferred compounds of Embodiment 54 include those of Embodiment 55,i.e., compounds of Embodiment 54 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, piperidinyl, or pyrrolidinyl    ring, each of which is unsubstituted or substituted with 1 or more    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    phenyl C₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, OH, ═O,    pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl    C₁-C₆ alkyl, phenyl, naphthyl, —OCH₂CH₂O—, or —OCH₂O—.

Preferred compounds of Embodiment 55 include those of Embodiment 56,i.e., compounds of Embodiment 55 where

-   R₁ is C₂-C₆ alkynyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 55 include those of Embodiment 57,i.e., compounds of Embodiment 55 where

-   R₁ is C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 55 include those of Embodiment 58,i.e., compounds of Embodiment 55 where

-   R₁ is C₁-C₆ alkenyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 51 include those of Embodiment 59,i.e., compounds of Embodiment 51 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,    morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆    alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl, furanyl, pyridyl,    pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl,    furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl    C₂-C₆ alkenyl, phenyl C₂-C₆ alkynyl, wherein the cyclic portion of    each of the above is unsubstituted or substituted with one or more    groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH,    phenyl C₁-C₆ alkyl wherein the phenyl is optionally substituted with    1, 2, 3, 4, or 5 groups that are independently selected from C₁-C₄    alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy    C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or    —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 59 include those of Embodiment 60,i.e., compounds of Embodiment 59 where

-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is phenyl or pyridyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃ or OCF₃.

Preferred compounds of Embodiment 60 include those of Embodiment 61,i.e., compounds of Embodiment 60 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl C₁-C₆    alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, phenyl,    furanyl, pyridyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl,    imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl,    phenyl C₁-C₆ alkyl, wherein the cyclic portion of each of the above    is unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 61 include those of Embodiment 62,i.e., compounds of Embodiment 61 where

-   R₁ is C₂-C₆ alkynyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 61 include those of Embodiment 63,i.e., compounds of Embodiment 61 where

-   R₁ is C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 61 include those of Embodiment 64,i.e., compounds of Embodiment 61 where

-   R₁ is C₁-C₆ alkenyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 51 include those of Embodiment 65,i.e., compounds of Embodiment 51 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, or C₃-C₆ cycloalkyl,    wherein the cycloalkyl is unsubstituted or substituted with one or    more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂,    CN, OH, phenyl C₁-C₆ alkyl wherein the phenyl is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and    alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;        wherein the cycloalkyl portion of R₄ and R₅ is further        optionally substituted with ═O, ═N-OH, or ═N—OCH₃.

Preferred compounds of Embodiment 65 include those of Embodiment 66,i.e., compounds of Embodiment 65 where

-   R₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, each of which is    unsubstituted or substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkahoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl);    -   R₁₀ is phenyl or pyridyl, each of which is optionally        substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H,        CN, NO₂, CF₃ or OCF₃.

Preferred compounds of Embodiment 66 include those of Embodiment 67,i.e., compounds of Embodiment 66 where

-   R₁ is C₂-C₆ alkynyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 66 include those of Embodiment 68,i.e., compounds of Embodiment 66 where

-   R₁ is C₁-C₆ alkyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 66 include those of Embodiment 69,i.e., compounds of Embodiment 66 where

-   R₁ is C₁-C₆ alkenyl substituted with 1, 2, or 3 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl,    -   wherein the phenyl is optionally substituted with 1 or more        groups that are independently selected from C₁-C₄ alkyl, C₁-C₄        alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, or 2 groups that are        independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 65 include those of Embodiment 70,i.e., compounds of Embodiment 65 where R₁ is halogen.

Preferred compounds of Embodiment 50 include those of Embodiment 70A,i.e., compounds of Embodiment 50 where Z is a bond.

Preferred compounds of Embodiment 50 include those of Embodiment 70B,i.e., compounds of Embodiment 50 where Z is —CH₂—.

Preferred compounds of Embodiment 50 include those of Embodiment 70C,i.e., compounds of Embodiment 50 where Z is —NH—.

Preferred compounds of Embodiment 50 include those of Embodiment 70D,i.e., compounds of Embodiment 50 where Z is —S— or —SO₂—.

Preferred compounds of Embodiment 50 include those of Embodiment 70E,i.e., compounds of Embodiment 50 where Z is —N(C₁-C₄ alkyl)-. In anotheraspect, Z is —N(C₁-C₂ alkyl)-. In still another aspect, Z is —N(C₂-C₃alkyl)-.

Preferred compounds of Embodiment 50 include those of Embodiment 70F,i.e., compounds of Embodiment 50 where Z is —SO₂NH—, or —SO₂N(C₁-C₄alkyl)-.

In still another aspect, the invention provides compounds according toembodiment 50, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiment 50, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiment 50, wherein R₂₁ is amino, monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of embodiment50, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiment50, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiment50, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiment50, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiment50, wherein R₂₁ is phenyl, which is substituted with 1-5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiment 50, wherein R₂₁ is pyridyl or pyrimidyl, each of which isoptionally substituted with 1-5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (inone aspect, CF₃), or haloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiment 50, wherein R₂₁ is indolyl or (iso)quinolinyl, each of whichis optionally substituted with 1-5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (inone aspect, CF₃), or haloalkoxy (in one aspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiment50, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, or C₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds ofembodiment 50, wherein R₂₁ is —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), or—C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 51 include those of Embodiment 71,i.e., compounds of Embodiment 51 where

Z is a bond;

-   R₁ is phenyl, naphthyl, thienyl, furanyl, indolyl, pyridyl,    pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl,    benzofuranyl, piperidinyl, pyrrolidinyl, piperazinyl, or    morpholinyl, each of which is unsubstituted or substituted with 1,    2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl, halogen,    C₁-C₆ alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, heteroaryl selected from    pyridyl, pyrimidyl, pyrazinyl, indolyl, thienyl, furanyl, pyrrolyl,    and benzimidazolyl, heterocycloalkyl selected from piperidinyl,    pyrrolidinyl, piperazinyl, morpholinyl, and phenyl, naphthyl,    wherein the heteroaryl, heterocycloalkyl, phenyl and naphthyl groups    are optionally substituted with or phenyl, which is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃, and OCF₃,    wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); and    -   R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl,        quinolinyl, pyrimidyl, furanyl, indolyl, C₃-C₈ cycloalkyl,        wherein the cyclic portions are optionally substituted with        halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄        haloalkyl, or C₁-C₄ haloalkoxy;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₁        and R₁₀ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 71 include those of Embodiment 72,i.e., compounds of Embodiment 71 where

-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, imidazolidinyl, or    pyrrolidinyl ring, each of which is unsubstituted or substituted    with 1 or more groups that are independently C₁-C₄ alkyl, C₁-C₄    alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆ alkanoyl, OH, pyridyl,    pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl, pyrazinyl C₁-C₄ alkyl,    phenyl, —OCH₂CH₂O—, —OCH₂O—,    -   wherein the pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₆        alkyl, and phenyl groups are unsubstituted or substituted with 1        or more groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, CF₃ or OCF₃.

Preferred compounds of Embodiment 72 include those of Embodiment 73,i.e., compounds of Embodiment 72 where

-   R₁ is phenyl which is unsubstituted or substituted with 1, 2, 3, 4,    or 5 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆    alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆        alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 73 include those of Embodiment 74,i.e., compounds of Embodiment 73 where

-   R₂ and R₃ are both H; and-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring, each of    which is substituted with 1 or more groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆    alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl,    pyrazinyl C₁-C₄ alkyl, phenyl, —OCH₂CH₂O—, or —OCH₂O—.

Preferred compounds of Embodiment 72 include those of Embodiment 75,i.e., compounds of Embodiment 72 where

-   R₁ is thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl,    pyrazinyl, triazolyl, imidazolyl, benzofuranyl, piperidinyl,    pyrrolidinyl, piperazinyl, or morpholinyl, each of which is    unsubstituted or substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl) —NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); and    -   wherein the heterocycloalkyl portion of R₁₀ is further        optionally substituted with ═O, ═N—OH, or ═N—OCH₃.

Preferred compounds of Embodiment 75 include those of Embodiment 76,i.e., compounds of Embodiment 75 where

-   R₂ and R₃ are both H; and-   R₄ and R₅ and the nitrogen to which they are attached form a    piperazinyl, morpholinyl, piperidinyl, or pyrrolidinyl ring, each of    which is substituted with 1 or more groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆    alkanoyl, OH, pyridyl, pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl,    pyrazinyl C₁-C₄ alkyl, phenyl, —OCH₂CH₂O—, or —OCH₂O—.

Preferred compounds of Embodiment 76 include those of Embodiment 77,i.e., compounds of Embodiment 76 where

-   R₁ is thienyl optionally substituted with 1, 2, 3, or 4 groups that    are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl).

Preferred compounds of Embodiment 76 include those of Embodiment 78,i.e., compounds of Embodiment 76 where

-   R₁ is benzofuranyl optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN,    CO₂H, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl, which is optionally substituted with 1, 2,    3, 4, or 5 groups that are independently selected from C₁-C₄ alkyl,    C₁-C₄ alkoxy, halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl).

Preferred compounds of Embodiment 71 include those of Embodiment 78,i.e., compounds of Embodiment 71 where

-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,    morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆    alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,    morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl    C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl, furanyl, pyridyl,    pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl,    furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl    C₂-C₆ alkenyl, phenyl C₂-C₆ alkynyl, or C₃-C₈ cycloalkyl, wherein    the cyclic portion of each of the above is unsubstituted or    substituted with one or more groups that are independently C₁-C₆    alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl,    C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆ alkyl wherein the phenyl    is optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen,    OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,    C₁-C₆ alkanoyl, NR₇R₈, or —C(O) NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 79 include those of Embodiment 80,i.e., compounds of Embodiment 79 where

-   R₁ is phenyl which is unsubstituted or substituted with 1, 2, 3, 4,    or 5 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆    alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,    —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, CF₃, OCF₃, NH₂, NH(C₁-C₆        alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 71 include those of Embodiment 80A,i.e., compounds of Embodiment 71 where

Z is a bond.

Preferred compounds of Embodiment 71 include those of Embodiment 80B,i.e., compounds of Embodiment 71 where Z is —CH₂—.

Preferred compounds of Embodiment 71 include those of Embodiment 80C,i.e., compounds of Embodiment 71 where wherein Z is —NH—.

Preferred compounds of Embodiment 71 include those of Embodiment 80D,i.e., compounds of Embodiment 71 where Z is —S— or —SO₂—.

Preferred compounds of Embodiment 71 include those of Embodiment 80e,i.e., compounds of Embodiment 71 where Z is —N(C₁-C₄ alkyl)-. In anotheraspect, Z is —N(C₁-C₂ alkyl)-. In still another aspect, Z is —N(C₂-C₃alkyl)-.

Preferred compounds of Embodiment 71 include those of Embodiment 80F,i.e., compounds of Embodiment 71 where Z is —SO₂NH—, or —SO₂N(C₁-C₄alkyl)-.

In still another aspect, the invention provides compounds according toembodiment 71, wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds accordingto embodiment 71, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds accordingto embodiment 71, wherein R₂₁ is amino, monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of embodiment71, wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of embodiment71, wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of embodiment71, wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of embodiment71, wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of embodiment71, wherein R₂₁ is phenyl, which is substituted with 1-5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiment 71, wherein R₂₁ is pyridyl or pyrimidyl, each of which isoptionally substituted with 1-5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (inone aspect, CF₃), or haloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds ofembodiment 71, wherein R₂₁ is indolyl or (iso)quinolinyl, each of whichis optionally substituted with 1-5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (inone aspect, CF₃), or haloalkoxy (in one aspect, OCF₃)).

In still another aspect, the invention provides compounds of embodiment71, wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, or C₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds ofembodiment 71, wherein R₂₁ is —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), or—C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 71 include those of Embodiment 81,i.e., compounds of Embodiment 71 where

-   R₂ and R₃ are both H; and-   R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆    alkyl, piperidinyl, pyrrolidinyl, morpholinyl, morpholinyl C₁-C₆    alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆ alkyl, phenyl,    furanyl, pyridyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl,    imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, thienyl C₁-C₆ alkyl,    phenyl C₁-C₆ alkyl, wherein the cyclic portion of each of the above    is unsubstituted or substituted with one or more groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆)    alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆    alkyl wherein the phenyl is optionally substituted with 1, 2, 3, 4,    or 5 groups that are independently selected from C₁-C₄ alkyl, C₁-C₄    alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl,    C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,    -   wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein        the C₁-C₆ alkyl is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆        alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)        (C₁-C₆ alkyl) or CO₂H;    -   wherein the heterocycloalkyl and the cycloalkyl portions of R₄        and R₅ are further optionally substituted with ═O, ═N—OH, or        ═N—OCH₃.

Preferred compounds of Embodiment 81 include those of Embodiment 82,i.e., compounds of Embodiment 81 where

-   R₁ is thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl,    pyrazinyl, triazolyl, imidazolyl, benzofuranyl, piperidinyl,    pyrrolidinyl, piperazinyl, or morpholinyl, each of which is    unsubstituted or substituted with 1, 2, 3, or 4 groups that are    independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, CF₃,    OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl) -NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl).

Preferred compounds of Embodiment 82 include those of Embodiment 83,i.e., compounds of Embodiment 82 where

-   R₁ is thienyl optionally substituted with 1, 2, 3, or 4 groups that    are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H,    CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl,    NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl, piperidinyl, or    phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,    halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 82 include those of Embodiment 84,i.e., compounds of Embodiment 82 where

-   R₁ is benzofuranyl optionally substituted with 1, 2, 3, or 4 groups    that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN,    CO₂H, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, pyridyl,    piperidinyl, or phenyl, which is optionally substituted with 1, 2,    3, 4, or 5 groups that are independently selected from C₁-C₄ alkyl,    C₁-C₄ alkoxy, halogen, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Preferred compounds of Embodiment 51 include those of Embodiment 85,i.e., compounds of Embodiment 51 where

-   R₄ and R₅ are independently H, methyl, or —CH₂-(furan-2-yl), or    C₃-C₆ cycloalkyl, wherein the cycloalkyl group is optionally    substituted with ═O, ═N—OH, or ═N—OCH₃.

The invention also provides pharmaceutical compositions comprising acompound of Formula A and at least one pharmaceutically acceptablesolvent, carrier, excipient, adjuvant or a combination thereof.

The invention further provides packaged pharmaceutical compositionscomprising a pharmaceutical composition of the invention in a containertogether with instructions on how to use the compound or composition.

The invention further provides methods of treating a disease orcondition related to cell differentiation comprising administering atherapeutically effective amount of a compound of Formula A to a patientin need of such treatment. In another embodiment, the patient is amammal. In a more preferred embodiment, the mammal is a human.

In preferred methods of the invention, the disease or condition iscancer, inflammation, arthritis, or angiogenesis.

Other preferred compounds of the invention include those of Embodiment91, i.e., compounds of embodiments 51-85 wherein X is —C(O)R₂₀, and R₂₀is OH.

Other preferred compounds of the invention include those of Embodiment92, i.e., compounds of embodiments 51-85, wherein X is —C(O)R₂₀, and R₂₀is C₁-C₆ alkoxy (in another aspect, C₁-C₄ alkoxy.)

Other preferred compounds of the invention include those of Embodiment93, i.e., compounds of embodiments 51-85, wherein X is —NR_(x)R_(y);wherein

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, phenyl C₁-C₄ alkoxycarbonyl, phenyl, naphthyl,    phenyl C₁-C₄ alkyl, —C(O)—phenyl, or —C(O)— naphthyl, wherein the    phenyl and naphthyl groups are optionally substituted with 1, 2, 3,    4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, CO₂H, NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, CF₃, or OCF₃; wherein,    -   within the definition of R_(x) and R_(y).    -   R₆ and R₇ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl,        C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of each is        unsubstituted or substituted with 1, 2, or 3, groups that are        independently halogen, OH, CF₃, OC F₃, NH₂, NH(C₁-C₆ alkyl) or        N(C₁-C₆ alkyl) (C₁-C₆ alkyl); or    -   R₆ and R₇ and the nitrogen to which they are attached form a        ring having from 5 to 6 members, wherein the ring optionally        contains 1-2 additional heteroatoms selected from N, O, and S,        where the ring is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, OH, halogen,        amino, NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 93 include those of Embodiment 94,i.e., compounds of Embodiment 93 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, C₁-C₆    alkoxycarbonyl, phenyl C₁-C₄ alkoxycarbonyl, phenyl, phenyl C₁-C₄    alkyl, or —C(O)-phenyl, wherein the phenyl group is optionally    substituted with 1, 2, 3, 4, or 5 groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CO₂H, NR₆R₇, —C(O)NR₆R₇,—-(C₁-C₄    alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, CF₃, or OCF₃.

Preferred compounds of Embodiment 94 include those of Embodiment 95,i.e., compounds of Embodiment 94 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, benzyl, or    —C(O)-phenyl, wherein the phenyl groups are optionally substituted    with 1, 2, 3, 4, or 5 groups that are independently C₁-C₄ alkyl,    C₁-C₄ alkoxy, halogen, CO₂H, NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, CF₃, or OCF₃.

Preferred compounds of Embodiment 93 include those of Embodiment 96,i.e., compounds of Embodiment 93 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, pyridyl,    pyrimidyl, pyrazinyl, benzofuranyl, indolyl, benzimidazolyl,    thienyl, furanyl, quinolinyl, or isoquinolinyl, wherein the ring    portions of the above are optionally substituted with 1, 2, 3, 4, or    5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,    CO₂H, NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, CF₃, or OCF₃.

Preferred compounds of Embodiment 96 include those of Embodiment 96A,i.e., compounds of Embodiment 96 where

-   R_(x) and R_(y) are independently H, C₁-C₄ alkyl, pyridyl,    pyrimidyl, pyrazinyl, thienyl, or furanyl, wherein the ring portions    of the above are optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H,    NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    CF₃, or OCF₃.

Preferred compounds of Embodiment 96 include those of Embodiment 96B,i.e., compounds of Embodiment 96 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, benzofuranyl,    indolyl, benzimidazolyl, quinolinyl, or isoquinolinyl, wherein the    ring portions of the above are optionally substituted with 1, 2, 3,    4, or 5 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,    halogen, CO₂H, NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R₇, CF₃, or OCF₃.

Preferred compounds of Embodiment 93 include those of Embodiment 97,i.e., compounds of Embodiment 93 where, wherein

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, pyridyl C₁-C₆    alkyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, benzofuranyl    C₁-C₆ alkyl, indolyl C₁-C₆ alkyl, benzimidazolyl C₁-C₆ alkyl,    thienyl C₁-C₆ alkyl, furanyl C₁-C₆ alkyl, quinolinyl C₁-C₆ alkyl, or    isoquinolinyl C₁-C₆ alkyl, wherein the ring portions of the above    are optionally substituted with 1, 2, 3, 4, or 5 groups that are    independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H, NR₆R₇,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, CF₃, or    OCF₃.

Preferred compounds of Embodiment 97 include those of Embodiment 97A,i.e., compounds of Embodiment 97 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, pyridyl C₁-C₆    alkyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, thienyl C₁-C₆    alkyl, or furanyl C₁-C₆ alkyl, wherein the ring portions of the    above are optionally substituted with 1, 2, 3, 4, or 5 groups that    are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H, NR₆R₇,    —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, CF₃, or    OCF₃.

Preferred compounds of Embodiment 97 include those of Embodiment 97B,i.e., compounds of Embodiment 97 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, benzofuranyl C₁-C₆    alkyl, indolyl C₁-C₆ alkyl, benzimidazolyl C₁-C₆ alkyl, quinolinyl    C₁-C₆ alkyl, or isoquinolinyl C₁-C₆ alkyl, wherein the ring portions    of the above are optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H,    NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄    alkyl)-C(O)NR₆R_(7,) CF₃, or OCF₃.

Preferred compounds of Embodiment 93 include those of Embodiment 98,i.e., compounds of Embodiment 93 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, —C(O)-pyridyl,    —C(O)-pyrimidyl, —C(O)-pyrazinyl, —C(O)-benzofuranyl, —C(O)-indolyl,    —C(O)-benzimidazolyl, —C(O)-thienyl, —C(O)-furanyl,    —C(O)-quinolinyl, or —C(O)-isoquinolinyl, wherein the ring portions    of the above are optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H,    NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    CF₃, or OCF₃.

Preferred compounds of Embodiment 98 include those of Embodiment 98A,i.e., compounds of Embodiment 98 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl, —C(O)-pyridyl,    —C(O)-pyrimidyl, —C(O)-pyrazinyl, —C(O)-thienyl, or —C(O)-furanyl,    wherein the ring portions of the above are optionally substituted    with 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,    C₁-C₆ alkoxy, halogen, CO₂H, NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄    alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇, CF₃, or OCF₃.

Preferred compounds of Embodiment 98 include those of Embodiment 98B,i.e., compounds of Embodiment 98 where

-   R_(x) and R_(y) are independently H, C₁-C₆ alkyl,    —C(O)-benzofuranyl, —C(O)-indolyl, —C(O)-benzimidazolyl,    —C(O)-quinolinyl, or —C(O)-isoquinolinyl, wherein the ring portions    of the above are optionally substituted with 1, 2, 3, 4, or 5 groups    that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, CO₂H,    NR₆R₇, —C(O)NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —(C₁-C₄ alkyl)-C(O)NR₆R₇,    CF₃, or OCF₃.

Embodiment 99 includes compounds of embodiments 93, 94, 95, 96, 96A,96B, 97, 97A, 97B, 98, 98A, and 98B, wherein, within the definition ofR_(x) and R_(y).

-   R₆ and R₇ and the nitrogen to which they are attached form a ring    having from 5 to 6 members, wherein the ring optionally contains 1-2    additional heteroatoms selected from N, O, and S, where the ring is    optionally substituted with 1, 2, or 3 groups that are independently    C₁-C₄ alkyl, C₁-C₄ alkoxy, OH, halogen, amino, NH(C₁-C₆ alkyl), or    N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Preferred compounds of Embodiment 99 include those of Embodiment 100,i.e., compounds of Embodiment 99 where, within the definition of R_(x)and R_(y),

-   R₆ and R₇ and the nitrogen to which they are attached form a ring    that is pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, oxazolyl,    isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolidinyl,    pyrrolidinyl, pyrrolyl, piperidinyl, piperazinyl, or oxazolidinyl,    each of which is optionally substituted with 1, 2, or 3 groups that    are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, OH, halogen, amino,    NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆ alkyl)

Embodiment 101 includes compounds of embodiments 93, 94, 95, 96, 96A,96B, 97, 97A, 97B, 98, 98A, and 98B, wherein, within the definition ofR_(x) and R_(y),

-   R₆ and R₇ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl, C₁-C₆    alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted    or substituted with 1, or 2 groups that are independently halogen,    OH, CF₃, OCF₃, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

Embodiment 102 includes compounds of embodiments 93, 94, 95, 96, 96A,96B, 97, 97A, 97B, 98, 98A, 98B, 99, 100, and 101 wherein, within thedefinition of R_(x) and R_(y), R_(x) is H or C₁-C₄ alkyl.

In another aspect, the invention provides compounds according to any ofthe preceding embodiments wherein at least one of A₁ and A₂ is N. Inanother embodiment, both A₁ and A₂ are N.

In yet another aspect, the invention provides compounds according to anyone of the preceding embodiments wherein at least one of

is a double bond. In a more preferred aspect, both

are double bonds.

In still another aspect, the invention provides compounds according toany one of the preceding embodiments wherein both

are single bonds and A₂ is NH or N(C₁-C₄ alkyl).

In yet still another aspect, at least one of R₂, R₂′ and R₃ is hydrogen.In another aspect, two of R₂, R₂′ and R₃ are hydrogen. In still anotheraspect, R₂ is methyl or halogen (in still another aspect, the halogen ischloro or bromo.)

In another aspect, R₂, R₂′, R₂₁, and R₃ are hydrogen.

In still another aspect, the invention provides compounds of formula A,wherein R₂₁ is H.

In yet still another aspect, the invention provides compounds of formulaA, wherein R₂₁ is CN.

In still yet another aspect, the invention provides compounds of formulaA, wherein R₂₁ is amino, monoalkylamino, or dialkylamino.

In yet another aspect, the invention provides compounds of formula A,wherein R₂₁ is OH.

In still another aspect, the invention provides compounds of formula A,wherein R₂₁ is phenyl.

In still another aspect, the invention provides compounds of formula A,wherein R₂₁ is pyridyl.

In still another aspect, the invention provides compounds of formula A,wherein R₂₁ is halogen.

In yet another aspect, the invention provides compounds of formula A,wherein R₂₁ is phenyl, which is substituted with 1-5 groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄alkyl, haloalkyl (in one aspect, CF₃), or haloalkoxy (in one aspect,OCF₃)).

In yet still another aspect, the invention provides compounds of formulaA, wherein R₂₁ is pyridyl or pyrimidyl, each of which is optionallysubstituted with 1-5 groups that are independently C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (in one aspect,CF₃), or haloalkoxy (in one aspect, OCF₃)).

In yet still another aspect, the invention provides compounds of formulaA, wherein R₂₁ is indolyl or (iso)quinolinyl, each of which isoptionally substituted with 1-5 groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, OH, hydroxyl C₁-C₄ alkyl, haloalkyl (inone aspect, CF₃), or haloalkoxy (in one aspect, OCF₃)).

In still another aspect, the invention provides compounds of formula A,wherein R₂₁ is C₁-C₆ alkyl, C₂-C₆ alkynyl, or C₂-C₆ alkenyl.

In still yet another aspect, the invention provides compounds of formulaA, wherein R₂₁ is —C(O)NH₂, —C(O)NH(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl)(C₁-C₆ alkyl).

In another aspect, the invention encompasses a method of treating cancercomprising administering to a patient in need thereof, apharmaceutically acceptable amount of a compound or salt of formula A ora pharmaceutical composition comprising a compound or salt of formula A.

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached to the parent molecular moiety through an oxygenbridge. Examples of alkoxy groups include, for example, methoxy, ethoxy,propoxy and isopropoxy.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, 1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examplesof aryl groups include phenyl, naphthyl, and anthracenyl. More preferredaryl groups are phenyl and naphthyl. Most preferred is phenyl.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. More preferred are C₃-C₆ cycloalkyl groups.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine.

The term “heterocycloalkyl” refers to a ring or ring system containingat least one heteroatom selected from nitrogen, oxygen, and sulfur,wherein said heteroatom is in a non-aromatic ring. The heterocycloalkylring is optionally fused to or otherwise attached to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/orphenyl rings. Preferred heterocycloalkyl groups have from 3 to 7members. More preferred heterocycloalkyl groups have 5 or 6 members.Examples of heterocycloalkyl groups include, for example,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl,tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl.Preferred heterocycloalkyl groups include piperidinyl, piperazinyl,morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, andpyrrolidinonyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thienyl, 5,6,7,8-tetrahydroisoquinoline andpyrimidines.

Preferred examples of heteroaryl groups include thienyl, benzothienyl,pyridyl, quinolyl, pyrazolyl, pyrimidyl, imidazolyl, benzimidazolyl,furanyl, benzofuranyl, dibenzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

The compounds of this invention may contain one or more asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates,chiral non-racemic or diastereomers. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent; chromatography,using, for example a chiral HPLC column; or derivatizing the racemicmixture with a resolving reagent to generate diastereomers, separatingthe diastereomers via chromatography, and removing the resolving agentto generate the original compound in enantiomerically enriched form. Anyof the above procedures can be repeated to increase the enantiomericpurity of a compound.

When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless otherwise specified, itis intended that the compounds include the cis, trans, Z- andE-configurations. Likewise, all tautomeric forms are also intended to beincluded.

The compounds of general Formula A may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula A and apharmaceutically acceptable carrier. One or more compounds of generalFormula A may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula A may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatincapsules, wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example peanut oil, liquid paraffin or oliveoil.

Formulations for oral use may also be presented as lozenges.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula A may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula A may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

For disorders of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical gel, spray,ointment or cream, or as a suppository, containing the activeingredients in a total amount of, for example, 0.075 to 30% w/w,preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs. The compounds of this invention can also beadministered by a transdermal device. Preferably topical administrationwill be accomplished using a patch either of the reservoir and porousmembrane type or of a solid matrix variety. In either case, the activeagent is delivered continuously from the reservoir or microcapsulesthrough a membrane into the active agent permeable adhesive, which is incontact with the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane. The transdermal patch may include the compound in a suitablesolvent system with an adhesive system, such as an acrylic emulsion, anda polyester patch. The oily phase of the emulsions of this invention maybe constituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,among others. The choice of suitable oils or fats for the formulation isbased on achieving the desired cosmetic properties, since the solubilityof the active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredients are dissolved or suspended insuitable carrier, especially an aqueous solvent for the activeingredients. The antiinflammatory active ingredients are preferablypresent in such formulations in a concentration of 0.5 to 20%,advantageously 0.5 to 10% and particularly about 1.5% w/w. Fortherapeutic purposes, the active compounds of this combination inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules having one or more of the carriers or diluents mentioned foruse in the formulations for oral administration. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, and/or various buffers. Other adjuvants and modes ofadministration are well and widely known in the pharmaceutical art.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient. The daily dose can be administered in one tofour doses per day. In the case of skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.Preferred non-human animals include domesticated animals.

The compounds of the present invention may be prepared by use of knownchemical reactions and procedures. Representative methods forsynthesizing compounds of the invention are presented below. It isunderstood that the nature of the substituents required for the desiredtarget compound often determines the preferred method of synthesis. Allvariable groups of these methods are as described in the genericdescription if they are not specifically defined below.

Methods of Preparation

General Procedure for Amide Coupling Reactions:

R₆ and R₇ are as defined above.

To 1 equiv. of carboxylic acid in DMF is added 1 equiv. of theappropriate amine. The reaction mixture is stirred and cooled to 0° C.in an ice bath. 1 equiv. of diethylcyanophosphonate and 2 equiv. oftriethylamine are then added. After stirring for 10 minutes at 0° C.,the reaction mixture is removed from the ice bath and stirred at roomtemperature for 18-24 hours. Once the reaction was complete, asdetermined by LC/MS, the reaction is concentrated to dryness. Theresulting residue is dissolved in DCM (15 mL) and washed with 0.1N HCl(1×15 mL) and water (2×15 mL). The organic layer is then dried oversodium sulfate, filtered, and concentrated in vacuo to afford the crudeproduct, which is purified via column chromatography to yield the finalproduct.

One of skill in the art will appreciate that other methods of forming anamide bond are available. For example, the acid may be converted to anacid chloride or an acid anhydride and then treated with the amine. Or,the acid may be treated with one or more coupling reagents, such as DCC(dicyclohexyl carbodiimide), DIC (1,3 diisopropyl carbodiimide), EDCI(1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride), BBC(1-benzotriazol-1-yloxy-bis(pyrrolidino)uronium hexafluorophosphate),BDMP (5-(1H-benzotriazol-1-yloxy)-3,4-dihydro-1-methyl 2H-pyrroliumhexachloroanitimonate), BOMI(benzotriazol-1-yloxy-N,N-dimethylmethaniminium hexachloroantimonate),HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate),HAPyU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uroniumhexafluorophosphate,HBTU=O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate,TAPipU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uroniumetrafluoroborate, AOP(O-(7-azabenzotriazol-1-yl)-tris(dimethylamino)phosphoniumhexafluorophosphate), BDP (benzotriazol-1-yl diethyl phosphate), BOP(1-benzotriazolyoxytris(dimethylamino)phosphonium hexafluorophosphate),PyAOP (7-azobenzotriazolyoxytris(pyrrolidino)phosphoniumhexafluorophosphate), PyBOP(1-benzotriazolyoxytris(pyrrolidino)phosphonium hexafluorophosphate),TDBTU(2-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate), TNTU(2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluroniumtetrafluoroborate), TPTU(2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate),TSTU (2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate), BEMT(2-bromo-3-ethyl-4-methyl thiazolium tetrafluoroborate), BOP-Cl(bis(2-oxo-3-oxazolidinyl)phosphinic chloride), BroP(bromotris(dimethylamino)phosphonium hexafluorophosphate), BTFFH(bis(tetramethylenefluoroformamidinium) hexafluorophosphate), ClP(2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate), DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one), Dpp-Cl(diphenylphosphinic chloride), EEDQ(2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline), FDPP(pentafluorophenyl diphenylphosphinate), HOTT(S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouroniumhexafluorophosphate), PyBroP (bromotris(pyrrolydino)phophoniumhexafluorophosphate), PyCloP (chlorotris(pyrrolydino)phophoniumhexafluorophosphate), TFFH (tetramethylfluoroformamidiniumhexafluorophosphate), TOTT(S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouroniumtetrafluoroborate).

General Procedure for Sonogashira Couplings:

-   R carries the same definition as R₄;-   R′ is 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,    halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, phenyl,    or naphthyl, wherein the phenyl and naphthyl groups are optionally    substituted with 1 or more groups that are independently selected    from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); or    -   R₆ and R₇ and the nitrogen to which they are attached form a        ring having from 5 to 8 members, wherein the ring optionally        contains 1-3 additional heteroatoms selected from N, O, and S,        where the ring is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,        amino, NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

A 8-Bromo-[1,6]naphthyridine-2-carboxylic acid amide, an optionallysubstituted acetylene (2.5 equiv), tetrakis(triphenylphosphine)palladium(0) (5 mol %), copper (I) iodide (25 mol %), and potassium carbonate(3.0 equiv) are dissolved in 5:1 DME: water. The reaction vessel ispurged with N₂ and stirred overnight at approximately 50° C. The solventis removed in vacuo and the residue purified by preparative TLC, orother methods known to those skilled in the art.

General Procedure for Buchwald-Type Couplings:

-   R′ is 1, 2, 3, 4, or 5 groups that are independently C₁-C₆ alkyl,    halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, C₁-C₄ haloalkyl, C₁-C₄    haloalkoxy, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆    alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, —C(O)NR₆R₇, phenyl,    or naphthyl, wherein the phenyl and naphthyl groups are optionally    substituted with 1 or more groups that are independently selected    from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, CF₃, and OCF₃, wherein    -   each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄        alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of        each is unsubstituted or substituted with 1, 2, or 3, groups        that are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆        alkyl); or    -   R₆ and R₇ and the nitrogen to which they are attached form a        ring having from 5 to 8 members, wherein the ring optionally        contains 1-3 additional heteroatoms selected from N, O, and S,        where the ring is optionally substituted with 1, 2, or 3 groups        that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, OH,        amino, NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆ alkyl).

A microwave pressure vial (Personal Chemistry) is charged with an8-bromo-[1,6]naphthyridine-2-carboxylic acid amide (1 equiv.), anoptionally substituted aniline or aminoheterocycle (4.0 equiv.),bis(dibenzylideneacetone)palladium (0) (7 mol %),2-(dicyclohexylphosphino) biphenyl (14 mol %), and sodium tert-butoxide(2.0 equiv). The reagents are suspended in toluene to a concentration of0.5 M (with regards to naphthyridine). The vessel is purged with N₂ andthen the reaction mixture is heated to 110° C. via microwave radiation.After 420 seconds, the reaction vessel is allowed to cool to roomtemperature and then filtered through a plug of glass wool. Theresulting filtrate is concentrated and purified by preparatory TLC, orother methods known to those skilled in the art.

Those having skill in the art will recognize that the starting materialsand reaction conditions may be varied, the sequence of the reactionsaltered, and additional steps employed to produce compounds encompassedby the present invention, as demonstrated by the following examples. Insome cases, protection of certain reactive functionalities may benecessary to achieve some of the above transformations. In general, theneed for such protecting groups as well as the conditions necessary toattach and remove such groups will be apparent to those skilled in theart of organic synthesis.

The disclosures of all articles and references mentioned in thisapplication, including patents, are incorporated herein by reference intheir entirety.

Structures were named using Name Pro IUPAC Naming Software, version5.09, available from Advanced Chemical Development, Inc., 90 AdelaideStreet West, Toronto, Ontario, M5H 3V9, Canada or with ChemDraw v. 6.02,which is available from Cambridgesoft.com in Cambridge, Mass.

General Procedure for Suzuki Coupling Reactions:

1 equiv. 8-bromo-2-substituted-1,6-naphthyridine, 0.02 equiv.dichlorobis(triphenylphosphine)palladium (II), 1 equiv. boronic acid,1.5 equiv. sodium carbonate and 7:3:2 DME:H₂O:EtOH (2-4 mL) are combinedin a microwavable reaction tube. The tube is sealed and irradiated inthe microwave at 140° C. for 500 seconds. The resulting reaction mixtureis cooled to room temperature and diluted with water (˜10-15 mL).

If final compound contains an acid, the reaction mixture is acidified topH 6-7 with 1N HCl, and filtered. The resulting solid is washed withwater (˜50 mL), dried, filtered, and concentrated in vacuo to afford thecrude product, which is purified by methods known in the art.

If final compound does not contain an acid, the aqueous layer isextracted with dichloromethane (4×20 mL). The dichloromethane layers arecombined, dried over sodium sulfate, filtered and concentrated in vacuoto afford the crude product, which is purified by methods known in theart.

CHEMISTRY EXAMPLES

The preparation of intermediates and compounds of the invention isillustrated further by the following examples, which are not to beconstrued as limiting the invention in scope or spirit to the specificprocedures and compounds described in them. In all cases, unlessotherwise specified, the column chromatography is performed using asilica gel solid phase.

Example 1 Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acidmethyl ester (2)

The starting acid, 8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1), isprepared essentially according to the procedure described in J. Med.Chem. 1999, 42, 3023-3025 and the references cited therein.

8-Bromo-[1,6]naphthyridine-2-carboxylic acid methyl ester (2) isprepared by combining compound 1 (1 equiv.), cesium carbonate (1.1equiv.) and methyl iodide (1.1 equiv.) in DMF (10 mL) and stirring for16 hrs. at room temperature. The reaction is concentrated in vacuo togive a brown solid, which is dissolved in EtOAc (50 mL) and washed withwater (2×50 mL). The EtOAc layer is dried over sodium sulfate, filtered,and concentrated in vacuo to afford a purple solid. The crude product ispurified via silica gel chromatography (EtOAc) to yield (2) as a yellowsolid, 65%, LC/MS (M+H) 269.0.

Example 2 Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide (3)

8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1) is stirred in DMF (20mL) and furfurylamine (1 equiv.) is added. The reaction mixture iscooled to 0° C. (ice bath) and diethylcyanophosphonate (1 equiv.) isadded followed immediately by triethylamine (2 equiv.). The reactionmixture is removed from the ice bath and stirred at room temperature for26 hrs. The mixture is diluted with water (50 mL) and extracted withmethylene chloride (3×50 mL). The combined organic layers are dried oversodium sulfate, filtered, and concentrated in vacuo to afford a tansolid, which is purified via silica gel chromatography (1:1;hexanes:EtOAc to 1:3.) LC/MS (M+H) 332.1.

Example 3 Preparation of5-{2-[(Furan-2-ylmethyl)-carbamoyl]-[1,6]naphthyridin-8-yl}thiophene-2-carboxylicacid (4)

Compound 3 (above, 1 equiv.), 5-(dihydroxylboryl)-2-thiophene carboxylicacid (1 equiv.), dichloro(bistriphenylphosphine)palladium (II) (0.02equiv.), and sodium carbonate (1.5 equiv.) are combined with 7:3:2;DME:water:methanol (4 mL) in a microwavable reaction tube. The reactionmixture is irradiated in the microwave at 140° C. for 300 seconds andthen cooled to room temperature. The crude mixture is concentrated invacuo, affording a green-brown solid. Purification via silica gelchromatography (EtOAc to 4:1; EtOAc:methanol containing 1% acetic acid)affords a bright yellow solid. LC/MS (M+H) 340.2.

Example 4

The following compounds are prepared essentially according to theprocedures described above.

Ex. No. Name Data Structure 58-[5-(2-Dimethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-carboxylicacid (furan-2-ylmethyl)-amide brownish-yellowsolid: LC/MS(M + H)450.6

6 8-[5-(2-Diethylamino- brownish- ethylcarbamoyl)-thiophen-2- yellowyl]-[1,6]naphthyridine-2- solid; LC/MS carboxylic acid (furan-2- (M + H)ylmethyl)-amide 478.3. 7 8-Bromo-[1, yellow 6]naphthyridine-2-carboxylicsolid; LC/MS acid cyclopropylamide (M + H) 293.1 85-(2-Cyclopropylcarbamoyl- bright [1,6]naphthyridin-8-yl)- yellowthiophene-2-carboxylic acid solid, LC/MS (M + H) 340.2. 98-[5-(2-Dimethylamino- yellow ethylcarbamoyl)-thiophen-2- pseudo-yl]-[1,6]naphthyridine-2- solid, LC/MS carboxylic acid (M + H)cyclopropylamide 410.4. 10 8-[5-(2-Diethylamino- yellowethylcarbamoyl)-thiophen-2- solid, yl]-[1,6]naphthyridine-2- LC/MS (M +carboxylic acid H) 438.3. cyclopropylamide

Example 11 Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acidchloride

Oxalyl chloride (1.5 equiv.) is added drop wise to a slurry of8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1 equiv., in 20 mL DMF) at0° C. (ice bath) and stirred for 30 minutes. The reaction mixture isremoved from the ice bath, stirred at room temperature for 3 h and thenconcentrated in vacuo to give a greenish colored solid, which is usedimmediately without further purification.

Example 12 Preparation of 8-Bromo-[1,6]naphthyridine-2-carboxylic acidmethylamide

2.0 M Methylamine in ethanol is added to compound 11 and the reactionmixture is stirred for 20 h at room temperature. The reaction isconcentrated in vacuo to give a greenish-brown solid that is purifiedvia silica gel chromatography (EtOAc) to give compound 12 as a yellowsolid, LC/MS (M+H) 266.9.

Example 13 Preparation of5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic acid

The desired compound is prepared essentially using the proceduredescribed in Example 3. The product is a yellow solid, LC/MS (M+H)314.16.

Example 14 Preparation of5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic acidchloride

The desired compound is prepared essentially using the proceduredescribed in Example 11. The product is a yellow paste that is usedimmediately without further purification.

Example 15 Preparation of5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic acidamide

The compound is prepared by stirring compound 14 in 7N ammonia inmethanol (8 mL) at room temperature for 19 h. The reaction mixture isconcentrated in vacuo to afford a crude yellow solid. Purification viasilica gel chromatography (CHCl₃/MeOH/NH4OH 80/18/2) affords the desiredcompound as a bright yellow solid, LC/MS (M+H) 313.4.

8-Thiophen-2-yl-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide (1.0 equiv.) was stirred in methylene chloride(2.0 mL) under nitrogen at 0° C. (ice bath) and meta-chloroperoxybenzoicacid (1.0 equiv.) was added over 10 minutes. The reaction was warmed toroom temperature and stirred for 18 hours. LC/MS indicated the N-oxideas the major product. The reaction mixture was concentrated in vacuo toafford an orange solid and used in the next reaction without furtherpurification. LC/MS (M+H) 352.2.

6-N-Oxo-8-thiophen-2-yl-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide (1.0 equiv.) was combined with phosphorousoxychloride (8.0 mL) and refluxed for 2 hours and stirred an additional18 hours at room temperature. The reaction mixture was poured onto ice(25 g) and stirred for 20 minutes. The resulting brown precipitate wasfiltered to yield the product as a brown solid. LC/MS (M+H) 370.2.

5-Chloro-8-thiophen-2-yl-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide (1.0 equiv.) was combined with methylamine (10equiv., 2.0 M in methanol) and irradiated in a microwave at 100° C. for600 seconds. The reaction mixture was diluted with methanol (5 mL) andsonicated. The insolubles were filtered and the filtrate was evaporatedto dryness to yield the expected product as an orange oil. LC/MS (M+H)365.2.

The following compounds are prepared essentially according to themethods and procedures described above.

Ex. No. Name Data 165-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylicacidmethylamide bright yellowsolid, LC/MS(M + H) 327.4.

17 8-[5-(3-Morpholin-4-yl- yellow solid, propylcarbamoyl)-thiophen-LC/MS (M + H) 2-yl]-[1,6]naphthyridine- 440.3. 2-carboxylic acidmethylamide 18 8-Thiophen-3-yl[1,6]- tan solid,naphthyridine-2-carboxylic LC/MS (M + H) acid 257.1. 198-Thiophen-3-yl[1,6]- orange solid, naphthyridine-2-carboxylic LC/MS(M + H) acid (furan-2-ylmethyl)- 336.2. amide 20 8-Thiophen-3-yl[1,6]-orange solid, naphthyridine-2-carboxylic LC/MS (M + H) acidfuran-2-ylmethyl- 351.2. methyl-amide 218-Thiophen-3-yl[1,6]-naphthyridine-2-carboxylicacid cyclopropylamidelight, yellowsolid, LC/MS(M + H) 296.2.

22 8-Thiophen-3-yl[1,6]- tan solid, naphthyridine-2-carboxylic LC/MS(M + H) acid methylamide 270.1. 23 8-Thiophen-3-yl[1,6]- light, yellownaphthyridine-2-carboxylic solid, 58%, acid (2-hydroxy- LC/MS (M + H)cyclohexyl) amide 354.2. 24 8-Thiophen-3-yl[1,6]- white solid,naphthyridine-2-carboxylic LC/MS (M + H) acid (2-oxo- 354.2.cyclohexyl)amide prepared via Dess-Martin oxidation of compound 23 258-Thiophen-3-yl- off-white [1,6]naphthyridine-2- solid, 27%, carboxylicacid amide LC/MS (M + H) 256.3. Prepared from compound 18 268-Thiophen-3-yl-[1,6]naphthyridine-2-carboxylicacid(tetrahydro-furan-2-ylmethyl)-amide off-whitesolid, LC/MS(M + H)340.2.

27 8-Phenyl[1,6]- yellow solid, naphthyridine-2-carboxylic LC/MS (M + H)acid 251.2. 28 8-Phenyl[1,6]- orange pseudo- naphthyridine-2-carboxylicsolid, LC/MS acid (furan-2-ylmethyl)- (M + H) 330.2. amide 298-Phenyl[1,6]- orange pseudo- naphthyridine-2-carboxylic solid, 73%,acid furan-2-ylmethyl- LC/MS (M + H) methyl-amide 344.3. 308-Phenyl[1,6]- white solid, naphthyridine-2-carboxylic LC/MS (M + H)acid cyclopropylamide 290.2. 31 8-Phenyl[1,6]- LC/MS (M + H)naphthyridine-2-carboxylic 250.2. acid amide 32 8-Bromo[1,6]- light,yellow naphthyridine-2-carboxylic solid, LC/MS acid (2-hydroxy- (M + H)350.2. cyclohexyl) amide 33 8-Bromo[1,6]-naphthyridine-2-carboxylicacid(2-oxo-cyclohexyl)amide white solid,LC/MS (M + H)348.1.preparedviaDess-Martinoxidation ofcompound 32

34 8-Phenyl[1,6]- white solid, naphthyridine-2-carboxylic LC/MS (M + H)acid (2-hydroxy- 348.3. cyclohexyl) amide 35 8-Phenyl[1,6]- off-whitenaphthyridine-2-carboxylic solid, LC/MS acid (2-oxo- (M + H) 346.1.cyclohexyl) amide

Example 36 Preparation of8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acidcyclopropylamide

8-Bromo-[1,6]naphthyridine-2-carboxylic acid cyclopropylamide, acetylene(2.5 equiv), tetrakis(triphenylphosphine)palladium (0) (5 mol %), copper(I) iodide (25 mol %), and potassium carbonate (3.0 equiv) are dissolvedin 5:1 DME:water. The reaction vessel is purged with N₂ and stirredovernight at 50° C. The solvent is removed in vacuo and the residuepurified by preparative TLC (EtOAc) to afford the desired product as anoff-white solid, LC/MS (M+H) 268.2.

Ex. No. Name Data 378-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acid amideoff-whitesolid, LC/MS(M + H) 228.2.

38 8-(3-Hydroxy-prop-1- off-white ynyl-[1, solid, LC/MS6]naphthyridine-2- (M + H) 308.2. carboxylic acid (furan- 2-ylmethyl)amide 39 (3-{2-[(Furan-2- off-white ylmethyl)-carbamoyl]- solid, LC/MS[1,6]naphthyridin-8- (M + H) 407.3. yl}-prop-2-ynyl)- carbamic acidtert- butyl ester 40 8-Phenylethynyl-[1, off-white 6]naphthyridine-2-solid, LC/MS carboxylic acid (furan- (M + H) 354.2. 2-ylmethyl)-amide 418-Ethynyl-[1, off-white 6]naphthyridine-2- solid, LC/MS carboxylic acid(furan- (M + H) 278.1. 2-ylmethyl)-amide

The following compounds were prepared essentially according to themethod described for the Buchwald-type coupling.

Ex. No. Name Data 428-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylicacid(furan-2-ylmethyl)-amide off-whitesolid,LC/MS (M +H)375.2.

43 8-para-Tolylamino- off-white [1,6]naphthyridine- solid, 2-carboxylicacid LC/MS (M + (furan-2-ylmethyl)- H) amide 359.2. 44 8-Phenylamino-[1,off-white 6]naphthyridine-2- solid, carboxylic acid LC/MS (M +(furan-2-ylmethyl)- H) amide 345.2. 45 8-(3- off-white Trifluoromethyl-solid, phenylamino0-[1, LC/MS (M + 6]naphthyridine-2- H) carboxylic acid413.2. (furan-2-ylmethyl)- amide 46 8-(4- off-white Trifluoromethyl-solid, phenylamino)-[1, LC/MS (M + 6]naphthyridine-2- H) carboxylic acid413.2. (furan-2-ylmethyl)- amide 478-(Pyridin-3-ylamino)-[1,6]naphthyridine-2-carboxylicacid(furan-2-ylmethyl)-amide off-whitesolid,LC/MS (M +H)346.2.

48 8-(Pyridin-4- off-white ylamino)-[1, solid, 6]naphthyridine-2- LC/MS(M + carboxylic acid H) (furan-2-ylmethyl)- 346.2. amide 498-(Pyrazin-2- off-white ylamino)-[1, solid, 6]naphthyridine-2- LC/MS(M + carboxylic acid H) (furan-2-ylmethyl)- 347.2. amide 508-(3,5-Dichloro- off-white phenylamino)-[1, solid, 6]naphthyridine-2-LC/MS (M + carboxylic acid H) (furan-2-ylmethyl)- 413.2. amide 518-(4-Methoxy- off-white phenylamino)-[1, solid, 6]naphthyridine-2- LC/MS(M + carboxylic acid H) cyclopropylamide 335.3. 528-(3,5-Dichioro-phenylamino)-[1,6]naphthyridine-2-carboxylicacidcyclopropylamide off-whitesolid,LC/MS (M +H)373.2.

53 8-(4-Methoxy- off-white phenylamino)-[1, solid, 6]naphthyridine-2-LC/MS (M + carboxylic acid H) amide 291.1. 54 8-[(Furan-2- yellowylmethyl)-amino]-[1, solid, 6]naphthyridine-2- LC/MS (M + carboxylicacid H) (furan-2-ylmethyl)- 389.3. amide 55 8-[(Pyridin-4- yellowylmethyl)-amino]-[1, solid, 6]naphthyridine-2- LC/MS (M + carboxylicacid H) (furan-2-ylmethyl)- 360.3. amide 56 8-[(Pyridin-2- yellowylmethyl)-amino]-(1, solid, 6]naphthyridine-2- LC/MS (M + carboxylicacid H) (furan-2-ylmethyl)- 360.3. amide 578-[(Pyridin-3-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylicacid(furan-2-ylmethyl)-amide yellowsolid,LC/MS (M +H)360.3.

58 8-(3-Methoxy- yellow benzylamino)-[1, solid, 6]naphthyridine-2- LC/MS(M + carboxylic acid H) (furan-2-ylmethyl)- 389.2. amide 598-Cyclopropylamino- yellow [1,6]naphthyridine- solid, 2-carboxylic acidLC/MS (M + (furan-2-ylmethyl)- H) amide 309.2. 60 8-Prop-2-ynylamino-yellow [1,6]naphthyridine- solid, 2-carboxylic acid LC/MS (M +(furan-2-ylmethyl)- H) amide 307.2. 61 8-(2-Oxo-pyrrolidin- yellow1-yl)-[1, solid, 6]naphthyridine-2- LC/MS (M + carboxylic acid H)(furan-2-ylmethyl)- 337.3. amide

Example 62 Preparation of (8-Bromo-[1,6]naphthyridin-2-yl)-carbamic acidtert-butyl ester

8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1 equiv.) is suspended intert-butanol (20 mL). Triethylamine (1.1 equiv.) and diphenylphosphorylazide (1.1 equiv.) are added and the reaction is warmed to reflux. Afterrefluxing for 2.5 hours, the reaction is allowed to cool and half thesolvent is removed by rotary evaporation. The residue is dissolved inethyl acetate (200 mL) and washed with saturated NaHCO₃ (50 mL). Theorganic phase is dried over magnesium sulfate, filtered and concentratedto afford the crude product. Silica gel chromatography (1:1EtOAc:hexanes) affords the desired BOC amine as a solid, LC/MS (M+H)324.1.

Example 63 Preparation of 8-Bromo-[1,6]naphthyridin-2-ylaminedihydrochloride

(8-Bromo-[1,6]naphthyridin-2-yl)-carbamic acid tert-butyl ester (1equiv.) is suspended in methanol (10 mL). Acetyl chloride (ca. 1 mL) isadded over 1 minute. After the reaction mixture cools to ambienttemperature, the solvent is brought briefly to reflux using a heat gun.The heat gun is applied twice more, at which point TLC (1:1EtOAc:hexanes) indicated complete reaction. Concentration, followed bytrituration twice with dry methanol affords the title compound as awhite solid, LC/MS (M+H) 224.1.

Example 64 Preparation of 1, 2, 3,4-Tetrahydro-[1,6]naphthyridine-2-carboxylic acid methyl ester

1,6]naphthyridine-2-carboxylic acid methyl ester (1 equiv.) and methanol(anhydrous, 5 mL) were combined in a reaction vessel under nitrogenatmosphere. Palladium, 5% wt. on calcium carbonate (1 equiv.) was addedand hydrogen gas was bubbled through the solution via balloon for 12 h.The reaction was passed through a short plug of silica to remove thecatalyst and the silica plug was washed with 20% methanol in DCM. Thesolvent was removed in vacuo to yield the title compound as a brownsolid weighing 12 mg (59%).

The following compounds are prepared essentially according to themethods, examples, and procedures described above.

Ex. No. Structure Name 65 methyl 8-bromo-1,6- naphthyridine-2-carboxylate 66 8-(3-thienyl)-1,6- naphthyridine-2- carboxylic acid 67

N-cyclopropyl-8-[5-({(2-(diethylamino)ethyl]amino}carbonyl)-2-thienyl]-1,6-naphthyridine-2-carboxamide68 8-phenyl-1,6- naphthyridine-2- carboxylic acid 69N-(2-furylmethyl)-8-{[4- (trifluoromethyl)phenyl]amino}-1,6-naphthyridine- 2-carboxamide 70 N-(2-furylmethyl)-8-[(4-methyiphenyl)amino]-1,6- naphthyridine-2- carboxamide 71 8-anilino-N-(2-furylmethyl)-1,6- naphthyridine-2- carboxamide 72

N-(2-furylmethyl)-8-{[3-(trifluoromethyl)phenyl]amino}-1,6-naphthyridine-2-carboxamide73 N-(2-furylmethyl)-8-[(4- methoxyphenyl)amino]-1,6- naphthyridine-2-carboxamide 74 N-(2-furylmethyl)-8-(3- hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2- carboxamide 75 8-(5-carboxy-2-thienyl)-1,6-naphthyridine-2- carboxylic acid 76 8-bromo-N-(2-oxocyclohexyl)-1,6- naphthyridine-2- carboxamide 77

N-(2-furylmethyl)-8-(pyridin-3-ylamino)-1,6-naphthyridine-2-carboxamide78 tert-butyl[3-(2-{[(2- furylmethyl)amino]carbonyl}-1,6-naphthyridin-8- yl)prop-2-yn-1- yl]carbamate 79 N-(2-furylmethyl)-8-(pyridin-4-ylamino)-1,6- naphthyridine-2- carboxamide 80 8-bromo-1,6-naphthyridine-2- carboxamide 81 8-(5-({[2- (diethylamino)ethyl]amino}carbonyl)-2-thienyl]-N- (2-furylmethyl)-1,6- naphthyridine-2-carboxamide 82

8-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-2-thienyl]-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide83 N-cyclopropyl-8-[5-({[2- (dimethylamino)ethyl]amino}carbonyl)-2-thienyl]- 1,6-naphthyridine-2- carboxamide 84 diethylN-(4-{[(8-bromo- 1,6-naphthyridin-2- yl)carbonyl]amino}benzoyl)glutamate 85 N-(2-furylmethyl)-8- (pyrazin-2-ylamino)-1,6-naphthyridine-2- carboxamide 86 N-(2-oxocyclohexyl)-8-(3- thienyl)-1,6-naphthyridine-2- carboxamide 87

N-(2-oxocyclohexyl)-8-phenyl-1,6-naphthyridine-2-carboxamide 888-(3-hydroxyprop-1-yn-1- yl)-1,6-naphthyridine-2- carboxamide 89N-cyclopropyl-8-(3- hydroxyprop-1-yn-1-yl)- 1,6-naphthyridine-2-carboxamide 90 N-(2-furylmethyl)-8- (phenylethynyl)-1,6-naphthyridine-2- carboxamide 91 8-ethynyl-N-(2- furyirnethyl)-1,6-naphthyridine-2- carboxamide 92

N-cyclopropyl-8-[(4-methoxyphenyl)amino]-1,6-naphthyridine-2-carboxamide93 8-brorno-N-cyclopropyl- 1,6-naphthyridine-2- carboxamide 948-bromo-N-(2- furylmethyl)-1,6- naphthyridine-2- carboxamide 95N-(2-furylmethyl)-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide 96N-cyclopropyl-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide 97

5-{2-[(cyclopropylamino)carbon-yl]-1,6-naphthyridin-8-yl}thiophene-2-carboxylicacid98 5-(2-{[(2- furylmethyl)amino]carbonyl}- 1,6-naphthyridin-8-yl)thiophene-2-carboxylic acid 99 N-methyl-8-(3-thienyl)-1,6-naphthyridine-2- carboxamide 100 8-(4-methoxyphenyl)-N-[(5-methylpyrazin-2- yl)methyl]-1,6- naphthyridine-2- carboxamide 1018-(4-methoxyphenyl)-2- (morpholin-4-ylcarbonyl)- 1,6-naphthyridine 102

2-[(4-benzylpiperazin-1-yl)carbonyl]-8-(4-methoxyphenyl)-1,6-naphthyridine103 8-phenyl-2-(piperidin-1- ylcarbonyl)-1,6- naphthyridine 104N-(3-morpholin-4- ylpropyl)-8-(3-thienyl)- 1,6-naphthyridine-2-carboxamide 105 2-(morpholin-4- ylcarbonyl)-8-(3- thienyl)-1,6-naphthyridine 106 N-[4- (methylsulfonyl)benzyl]- 8-(3-thienyl)-1,6-naphthyridine-2- carboxamide 107

8-(3-thienyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,6-naphthyridine-2-carboxamide108 1-{[8-(3-thienyl)-1,6- naphthyridin-2- yl]carbonyl}piperidin-4- ol109 N-(2-methoxyethyl)-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide110 N-cyclopropyl-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide 1118-(4-methoxyphenyl)-N-(3- morpholin-4-ylpropyl)- 1,6-naphthyridine-2-carboxamide 112

N-[3-(1H-imidazol-1-yl)propyl]-8-(4-methoxyphenyl)-1,6-naphthyridine-2-carboxamide113 8-(4-methoxyphenyl)-N- (pyridin-4-ylmethyl)-1,6- naphthyridine-2-carboxamide 114 8-(4-methoxyphenyl)-2- (piperidin-1-ylcarbonyl)-1,6-naphthyridine 115 N-benzyl-8-(4- methoxyphenyl)-1,6-naphthyridine-2- carboxamide 116 8-(4-methoxyphenyl)-N-(2-phenylethyl)-1,6- naphthyridine-2- carboxamide 117

8-(4-methoxyphenyl)-2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1,6-naphthyridine118 N-(1-benzylpiperidin-4- yl)-8-(4-methoxyphenyl)-1,6-naphthyridine-2- carboxamide 119 N-(2-methoxybenzyl)-8-(4-methoxyphenyl)-1,6- naphthyridine-2- carboxamide 120 N-[4-(dimethylamino)benzyl]-8- (4-methoxyphenyl)-1,6- naphthyridine-2-carboxamide 121 8-(4-methoxyphenyl)-N-[4- (methylsulfonyl)benzyl]-1,6-naphthyridine-2- carboxamide 122

8-(4-methoxyphenyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,6-naphthyridine-2-carboxamide123 N-(3-morpholin-4- ylpropyl)-8-phenyl-1,6- naphthyridine-2-carboxamide 124 N-[3-(1H-imidazol-1- yl)propyl]-8-phenyl-1,6-naphthyridine-2- carboxamide 125 N-[(5-methylpyrazin-2-yl)methyl]-8-phenyl-1,6- naphthyridine-2- carboxamide 126

2-(1,4-dioxa-8-azaspiro[4,5]dec-8-ylcarbonyl)-8-phenyl-1,6-naphthyridine127 8-phenyl-N-(pyridin-4- ylmethyl)-1,6- naphthyridine-2- carboxamide128 2-(morpholin-4- ylcarbonyl)-8-phenyl-1,6- naphthyridine 129N-benzyl-8-phenyl-1,6- naphthyridine-2- carboxamide 130 8-phenyl-N-(2-phenylethyl)-1,6- naphthyridine-2- carboxamide 131

8-phenyl-2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1,6-naphthyridine132 N-(4-chlorobenzyl)-8- phenyl-1,6-naphthyridine- 2-carboxamide 1332-[(4-benzylpiperazin-1- yl)carbonyl]-8-phenyl- 1,6-naphthyridine 134N-(1-benzylpiperidin-4- yl)-8-phenyl-1,6- naphthyridine-2- carboxamide135 N-(2-methoxybenzyl)-8- phenyl-1,6-naphthyridine- 2-carboxamide 136

N-[4-(methylsulfonyl)benzyl]-8-phenyl-1,6-naphthyridine-2-carboxamide137 8-phenyl-N-{[6- (trifluoromethyl)pyridin- 3-yl]methyl}-1,6-naphthyridine-2- carboxamide 138 N-(2-isopropoxybenzyl)-8-phenyl-1,6-naphthyridine- 2-carboxamide 139 N-[3-(1H-imidazol-1-yl)propyl]-8-(3-thienyl)- 1,6-naphthyridine-2- carboxamide 1402-(1,4-dioxa-8- azaspiro[4.5]dec-8- ylcarbonyl)-8-(3- thienyl)-1,6-naphthyridine 141

N-(pyridin-4-ylmethyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide 1422-(piperidin-1- ylcarbonyl)-8-(3- thienyl)-1,6- naphthyridine 143N-benzyl-8-(3-thienyl)- 1,6-naphthyridine-2- carboxamide 144N-(2-furylmethyl)-8-(3- thienyl)-1,6- naphthyridine-2- carboxamide 1452-[(4-pyridin-2- ylpiperazin-1- yl)carbonyl]-8-(3- thienyl)-1,6-naphthyridine 146

N-(4-chlorobenzyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide 1472-[(4-benzylpiperazin-1- yl)carbonyl]-8-(3- thienyl)-1,6- naphthyridine148 N-(1-benzylpiperidin-4- yl)-8-(3-thienyl)-1,6- naphthyridine-2-carboxamide 149 N-(2-methoxybenzyl)-8-(3- thienyl)-1,6- naphthyridine-2-carboxamide 150 2-({4-[(4,6- dimethoxypyrimidin-2-yl)methyl]piperazin-1- yl}carbonyl)-8-(3- thienyl)-1,6- naphthyridine151

N-(2-isopropoxybenzyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide 1521-{[8-(1-benzofuran-2- yl)-1,6-naphthyridin-2- yl]carbonyl}piperidin-4-ol 153 8-(1-benzofuran-2-yl)-N- (2-methoxyethyl)-1,6- naphthyridine-2-carboxamide 154 8-(1-benzofuran-2-yl)-N- cyclopropyl-1,6-naphthyridine-2- carboxamide 155 1-[(8-phenyl-1,6- naphthyridin-2-yl)carbonyl]piperidin-4- ol 156

N-(2-methoxyethyl)-8-phenyl-1,6-naphthyridine-2-carboxamide 157N-cyclopropyl-8-phenyl- 1,6-naphthyridine-2- carboxamide 1588-(1-benzofuran-2-yl)-N- (3-morpholin-4-ylpropyl)- 1,6-naphthyridine-2-carboxamide 159 8-(1-benzofuran-2-yl)-N- [3-(1H-imidazol-1-yl)propyl]-1,6- naphthyridine-2- carboxamide 1608-(1-benzofuran-2-yl)-N- [(5-methylpyrazin-2- yl)methyl]-1,6-naphthyridine-2- carboxamide 161

8-(1-benzofuran-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-1,6-naphthyridine162 8-(1-benzofuran-2-yl)-N- (pyridin-4-ylmethyl)-1,6- naphthyridine-2-carboxamide 163 8-(1-benzofuran-2-yl)-2- (morpholin-4-ylcarbonyl)-1,6-naphthyridine 164 8-(1-benzofuran-2-yl)-2- (piperidin-1-ylcarbonyl)-1,6-naphthyridine 165 8-(1-benzofuran-2-yl)-N- benzyl-1,6-naphthyridine-2-carboxamide 166

8-(1-benzofuran-2-yl)-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide167 8-(1-benzofuran-2-yl)-N- (2-phenylethyl)-1,6- naphthyridine-2-carboxamide 168 8-(1-benzofuran-2-yl)-N- (4-chlorobenzyl)-1,6-naphthyridine-2- carboxamide 169 8-(1-benzofuran-2-yl)-2-[(4-benzylpiperazin-1- yl)carbonyl]-1,6- naphthyridine 1708-(1-benzofuran-2-yl)-N- (1-benzylpiperidin-4-yl)- 1,6-naphthyridine-2-carboxamide 171

8-(1-benzofuran-2-yl)-N-(2-methoxybenzyl)-1,6-naphthyridine-2-carboxamide172 8-(1-benzofuran-2-yl)-N- [4- (methylsulfonyl)benzyl]-1,6-naphthyridine-2- carboxamide 173

8-(1-benzofuran-2-yl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,6-naphthyridine-2-carboxamide174 8-(1-benzofuran-2-yl)-N- (2-isopropoxybenzyl)-1,6- naphthyridine-2-carboxamideBiological EvaluationEndothelial Cell Activation:

Low passage normal human umbilical vein endothelial cells (HUVEC)(Clonetics) were seeded 20,000 cells per well into 96-well assay platesand incubated at 37° C. overnight in a 5% CO₂ atmosphere. The followingday, 10× test compounds and controls were added to the appropriate wellsand the treated cells returned to the incubator for one hour. Cells werethen activated by adding TNF-α to a final concentration of 1 ng/ml andincubating for an additional 4 hours. After activation, media wasremoved and the cell monolayer was fixed by adding 100 μl/well of 100%methanol. Expression of E-selectin was then determined by performing anELISA with an E-selectin-specific primary antibody. Compound activitywas determined by comparing E-selectin expression levels to the DMSO and10 μM Actinomycin D controls.

To test for specificity of compound action, the endothelial cells werealso activated with 1 ng/ml IL-1β or LPS. 18 hour activation was alsodone for all three agonist, but cell activation for the longeractivation was measured by determining expression of ICAM using anICAM-specific primary antibody for the ELISA readout.

TNF-α Activation of NFκB Response Element:

293T cells were transfected with an NFκB-Luc reporter construct (BDBiosystems) using FuGENE 6 transfection reagent (Roche). Aftertransfection, the cells were plated into 96-well plates and incubated at37° C. overnight in a 5% CO₂ atmosphere. The following day, 10×concentrations of test compounds and controls were added to theappropriate wells, and the cells were incubated for an additional hour.TNF-α was then added to a final concentration of 5 ng/ml, followed byadditional 4 hour incubation. After activation the media was removed and30 μl/well of reporter lysis buffer was added (Promega). Luciferaseactivity was determined by adding luciferase reaction buffer (Promega)to the plate and measuring light output with a Tecan GeniosPro platereader. Compound activity was determined by comparing light output toDMSO and 10 μM Actinomycin D controls.

LPS Activated TNF-α Release:

THP-1 cells were seeded into V-bottom 96-well plates at 5,000 cells perwell. Plates were then incubated overnight at 37° C., 5% CO₂. Cells werethen treated with 10× compounds, using DMSO and 10 μM Actinomycin-D ascontrols. Plates were incubated for 1 hr at 37° C., 5% CO₂. Cells werethen activated with 10× LPS (final concentration: 25 ng/ml) andincubated overnight at 37° C., 5% CO₂. The following day, assay plateswere centrifuged, and the supernatant transferred to ELISA plates fordetermination of TNF-α secretion by sandwich ELISA (BiosourceInternational).

TNF-α Activated IL-8 Release:

HL60 cells were seeded into V-bottom 96-well plates at 20,000 cells perwell and treated with test compounds ranging in concentration from 40 μMto 64 nM, using DMSO and 10 μM Actinomycin D as the controls. Plateswere incubated for 1 hour at 37° C., 5% CO₂. Cells were then activatedby addition of TNF-α (final concentration: 12.5 ng/ml). Plates wereincubated for an additional 4 hours at 37° C., 5% CO₂. Plates were thencentrifuged, and supernatant transferred to ELISA plates fordetermination of IL-8 secretion by sandwich ELISA.

Cell Proliferation Assays

A panel of cancer cell lines was obtained from the DCTP TumorRepository, National Cancer Institute (Frederick, Md.) or ATCC(Rockville, Md.). Cell cultures were maintained in Hyclone RPMI 1640medium (Logan, Utah) supplemented with 10% fetal bovine serum and 20 mMHEPES buffer, final pH 7.2, at 37° C. with a 5% CO2 atmosphere. Cultureswere maintained at sub-confluent densities. Human umbilical veinendothelial cells (HUVEC) were purchased from Clonetics, a division ofCambrex (Walkersville, Md.). Cultures were established fromcryopreserved stocks using Clonetics EGM-2 medium supplemented with 20mM HEPES, final pH 7.2, at 37° C. with a 5% CO₂ atmosphere.

For proliferation assays, cells were seeded with the appropriate mediuminto 96 well plates at 1,000-2,500 cells per well, depending on the cellline, and were incubated overnight. The following day, test compound,DMSO solution (negative control), or Actinomycin D (positive control)was added to the appropriate wells as 10× concentrated stocks preparedin phosphate buffered saline. The cell plates were then incubated for anadditional 2-5 days, depending on the cell line, to allow proliferationto occur. To measure cell density, 50 μL of WST-1 solution (RocheApplied Science, IN) diluted 1:5 in phosphate buffered saline was addedto each well, and the cells incubated for an additional 1-5 hrs., againdepending on the cell line. Optical density was determined for each wellat 450 nM using a Tecan GeniosPro plate reader (RTP, NC). The percentageof cell growth was determined by comparing the cell growth in thepresence of test compounds to the cells treated with DMSO vehicle(control, 100% growth) and cells treated with Actinomycin D (10 μM, 0%growth).

Immediately after the WST-1 determination, the medium was removed fromthe PC-3, NCl-H460 and HUVEC cell lines, and the plates stored at −80°C. Using these assay plates, relative amounts of DNA in each well weredetermined using the Cyquant DNA assay kit from R&D Systems (Eugene,Oreg.) following the manufacturer's directions. Results for eachcompound treatment were compared to DMSO vehicle control (100%) and 10μM Actinomycin D treated cells (0%). Table 2 contains the cellproliferation data for several exemplary compounds useful in the methodsof the invention.

Preferred compounds of the invention have activities of less than 20 μMin all of the assays described above.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the invention and that modifications may be made thereinwithout departing from the spirit or scope of the invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as invention, the following claims conclude thisspecification.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein each -----independently represents a single bond or a double bond; A₁ is N, or anN-oxide; A₂ is N, an N-oxide, NH, or N(C₁-C₆) alkyl; provided that when----- is a single bond, then A₂ is NH, or N(C₁-C₆) alkyl; X isNR_(x)R_(y), or —C(O)R₂₀; wherein R_(x) and R_(y) are independently H,C₁-C₆ alkyl, alkoxycarbonyl, arylalkoxycarbonyl, aryl, arylalkyl,—C(O)—aryl, heteroaryl, heteroarylalkyl, or —C(O) heteroaryl; Z is abond, —CH₂, —NH—, —O—, —N(C₁-C₆ alkyl)—, —S—, —S(O)—, —SO₂—, —SO₂NH—, or—SO₂N(C₁-C₆ alkyl)—; R₁ is C₁-C₆ alkanoyl, C₂-C₆ alkynyl, aryl,heteroaryl, heterocycloalkyl, or C₃-C₈ cycloalkyl, each of which isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, C₁-C₄haloalkyl, C₁-C₄ haloalkoxy, —OC(O) —C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,C₁-C₆ alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)—NR₆R₇, —C(O)NR₆R₇,phenyl, or naphthyl, wherein the phenyl and naphthyl groups areoptionally substituted with 1 or more groups that are independentlyselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, CF₃, and OCF₃,wherein each R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkyl portion of each isunsubstituted or substituted with 1, 2, or 3, groups that areindependently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NH₂,NH(C₁-C₆ alkyl) or N (C₁-C₆ alkyl) (C₁-C₆ alkyl); or R₆ and R₇ and thenitrogen to which they are attached form a ring having from 5 to 8members, wherein the ring optionally contains 1-3 additional heteroatomsselected from N, O, and S, where the ring is optionally substituted with1, 2, or 3 groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, amino, NH (C₁-C₆ alkyl), or N (C₁-C₆ alkyl) (C₁-C₆ alkyl); R₁₀is C₂-C₆ alkenyl, C₂-C₆ alkynyl, aryl, heteroaryl, or cycloalkyl,wherein the cyclic portions are optionally substituted with 1, 2, or 3groups that are independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH,CO₂H, CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; wherein theheterocycloalkyl and the cycloalkyl portions of R₁ and R₁₀ are furtheroptionally substituted with ═O, ═N—OH, or ═N—OCH₃; R₂, R₂′, and R₃ areindependently H, halogen, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl,—C(O)NH₂, —C(O)NH(C₁-C₆ alkyl) —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl), oraryl; R₂₀ is H, OH, C₁-C₆ alkoxy, or NR₄R₅; wherein R₄ and R₅ areindependently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆ alkyl, C₂-C₆ alkynyl,C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkylalkynyl, heterocycloalkyl, heterocycloalkylalkyl,heterocycloalkylalkenyl, heterocycloalkylalkynyl, aryl, heteroaryl,heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, arylalkyl,arylalkenyl, or arylalkynyl, wherein the cyclic portion of each of theabove is unsubstituted or substituted with one or more groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂— (C₁-C₆) alkyl,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, aryl C₁-C₆ alkyl, C₁-C₆alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or—C(O)NR₇R₈, wherein R₇ and R₈ are independently H or C₁-C₆ alkyl,wherein the alkyl is optionally substituted with 1, 2, or 3 groups thatare independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆ alkoxy, C₁-C₆alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H; orR₇ and R₈ and the nitrogen to which they are attached form a ring havingfrom 5 to 8 members, wherein the ring optionally contains 1-3 additionalheteroatoms selected from N, O, and S, where the ring is optionallysubstituted with 1, 2, or 3 groups that are independently C₁-C₆ alkyl,C₁-C₆ alkoxy, halogen, amino, NH(C₁-C₆ alkyl), or N(C₁-C₆ alkyl) (C₁-C₆alkyl); wherein the heterocycloalkyl and the cycloalkyl portions of R₄and R₅ are further optionally substituted with ═O, ═N—OH, or ═N—OCH₃; orR₄ and R₅ and the nitrogen to which they are attached form aheterocycloalkyl ring, which is unsubstituted or substituted with 1 ormore groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,aryl C₁-C₆ alkyl, C₁-C₆ alkanoyl, OH, ═O, heteroaryl, heteroarylalkyl,phenyl, naphthyl, —OCH₂-CH₂O—, —OCH₂O—, wherein the heteroaryl, phenyland naphthyl groups are unsubstituted or substituted with 1 or moregroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃ orOCF₃; R₂₁ is H, CN, amino, monoalkylamino, dialkylamino, OH, halogen,aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, —C(O)NH₂,—C(O)NH(C₁-C₆ alkyl), or —C(O)N(C₁-C₆ alkyl) (C₁-C₆ alkyl); providedthat when R₂₀ is NR₄R₅ and R₄ is C₁₋₆ alkyl, C₂₋₆ alkenyl or C₃₋₇cyoloalkyl optionally substituted with OH, halogen, amino, carboxyl orsaturated or unsaturated C₃₋₁₀ (carbocycle or heterocycle) optionallysubstituted with OH, halogen, amino, mercapto, carboxy, C₁₋₄ (alkyl,alkoxy, alkylthio, acyl, acyloxy or alkoxycarbonyl) optionallysubstituted with OH, halogen, amino or C₁₋₄ alkoxy; and C₃₋₇ cycloalkylfused to C₆₋₁₀ aryl optionally substituted with OH, halogen, amino,mercapto, carboxy, C₁₋₄ (alkyl, alkoxy, alkylthio, acyl, acyloxy oralkoxycarbonyl) optionally substituted with OH, halogen, amino or C₁₋₄alkoxy; R₅ is H, or C₁₋₄ alkyl; and (1) Z is a bond; and R₂ or R₃ is H,OH, halogen, amino, cyano, C₁₋₆ (alkyl, alkoxy, acyl, acyloxy oralkoxycarbonyl) optionally substituted with OH, halogen, amino or C₁₋₄alkoxy, and saturated or unsaturated C₃₋₁₀ (carbocycle or heterocycle)optionally substituted with OH, halogen, amino, mercapto, C₁₋₄alkylthio, C₁₋₄ alkoxycarbonyl, halo substituted C₁₋₄ alkyl orhalo-substituted C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or carboxy; or (2)Z is a bond; R₂ or R₃ is H, OH, halogen, amino, cyano, C₁₋₆ (alkyl,alkoxy, acyl, acyloxy or alkoxycarbonyl) optionally substituted with OH,halogen, amino or C₁₋₄ alkoxy, and saturated or unsaturated C₃₋₁₀(carbocycle or heterocycle) optionally substituted with OH, halogen,amino, mercapto, C₁₋₄ alkylthio, C₁₋₄ alkoxycarbonyl, halo substitutedC₁₋₄ alkyl or halo-substituted C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy orcarboxy; and R₄ and R₅ together form a saturated or unsaturated 5 or 6member heterocycle optionally fused to C₆₋₁₀ aryl or heteroaryl; then R₁is not OH, amino, cyano, C₁₋₆ (alkoxy, acyl, acyloxy or alkoxycarbonyl)optionally substituted with OH, halogen, amino or C₁₋₄ alkoxy, andsaturated or unsaturated C₃₋₁₀ (carbocycle or heterocycle) optionallysubstituted with OH, halogen, amino, mercapto, C₁₋₄ alkylthio, C₁₋₄alkoxycarbonyl, halo substituted C₁₋₄ alkyl or halo-substituted C₁₋₄alkoxy, C₁₋₄ alkyl, C₁₋₄ alkoxy or carboxy.
 2. A compound according toclaim 1, wherein R₁ is C₁-C₆ alkanoyl, C₂-C₆ alkynyl, phenyl, naphthyl,thienyl, furanyl, indolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl,triazolyl, imidazolyl, oxazolyl, isoxazolyl, benzofuranyl, 3,4dihydropyrimidin-2 (1H)—onyl, piperidinyl, pyrrolidinyl, piperazinyl,morpholinyl, thiomorpholinyl, S,S -dioxothiomorpholinyl, or C₃-C₈cycloalkyl, each of which is unsubstituted or substituted with 1, 2, 3,4, or 5 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆alkoxy, OH, ON, CO₂H, phenyl, naphthyl, wherein the phenyl and naphthylgroups are optionally substituted with 1 or more groups that areindependently selected from C₁-C₄ alkyl, C₁-C_(C) ₄ alkoxy, halogen, OH,CF₃, and OCF₃, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl,C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein Each R₆ and R₇ is independently H,C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkylportion of each is unsubstituted or substituted with 1, 2, or 3, groupsthat are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); R₁₀ is C₂-C₆alkenyl, C₂-C₆ alkynyl, phenyl, naphthyl, pyridyl, quinolinyl,pyrimidyl, furanyl, indolyl, benzofuranyl, thienyl, cycloalkyl, whereinthe cyclic portions are optionally substituted with halogen, C₁-C₆alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄haloalkoxy; wherein the heterocycloalkyl and the cycloalkyl portions ofR₁ and R₁₀ are further optionally substituted with ═O, ═N—OH, or═N—OCH₃.
 3. A compound according to claim 1, wherein R₂₀ is NR₄R₅;wherein R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxy C₁-C₆alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylC₁-C₆ alkyl, C₃-C₈ cycloalkyl C₂-C₆ alkenyl, cycloalkyl C₂-C₆ alkynyl,piperidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl,S,S-dioxothiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl,morpholinyl C₁-C₆ alkyl, thiomorpholinyl C₁-C₆ alkyl,S,S-dioxothiomorpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl,pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl, piperidinyl C₂-C₆alkenyl, pyrrolidinyl C₂-C₆ alkenyl, imidazolidinyl C₂-C₆ alkenyl,morpholinyl C₂-C₆ alkenyl, thiomorpholinyl C₂-C₆ alkenyl,S,S-dioxothiomorpholinyl C₂-C₆ alkenyl, tetrahydrofuranyl C₂-C₆ alkenyl,tetrahydrothienyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinylC₂-C₆ alkynyl, imidazolidinyl C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl,thiomorpholinyl C₂-C₆ alkynyl, S,S-dioxothiomorpholinyl C₂-C₆ alkynyl,tetrahydrofuranyl C₂-C₆ alkynyl, tetrahydrothienyl C₂-C₆ alkynyl,phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl, thienyl,imidazolyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, pyrimidyl C₁-C₆alkyl, pyrazinyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆alkyl, thienyl C₁-C₆ alkyl, heteroarylalkenyl, heteroarylalkynyl, phenylC₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, phenyl C₂-C₆ alkenyl, naphthyl C₂-C₆alkenyl, phenyl C₂-C₆ alkynyl, naphthyl C₂-C₆ alkynyl, wherein thecyclic portion of each of the above is unsubstituted or substituted withone or more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, —SO₂—(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN,OH, phenyl C₁-C₆ alkyl wherein the phenyl is optionally substituted with1, 2, 3, 4, or 5 groups that are independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R_(8,) or —C(O)NR₇R₈,wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein the C₁-C₆alkyl is optionally substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆ alkoxy, C₁-C₆alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H;wherein the heterocycloalkyl and the cycloalkyl portions of R₄ and R₅are further optionally substituted with ═O, ═N—OH, or ═N—OCH₃; or R₄ andR₅ and the nitrogen to which they are attached form a piperazinyl,morpholinyl, piperidinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl,S,S,-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, ring, which isunsubstituted or substituted with 1 or more groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, phenyl C₁-C₆ alkyl,naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, OH, ═O, pyridyl, pyrimidyl,pyrazinyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, phenyl,naphthyl, —OCH₂CH₂O—, —OCH₂O—, wherein the pyridyl, pyrimidyl,pyrazinyl, pyrimidyl C₁-C₆ alkyl, phenyl and naphthyl groups areunsubstituted or substituted with 1 or more groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.
 4. Acompound according to claim 1, wherein R₁ is C₁-C₆ alkanoyl, C₂-C₆alkynyl, phenyl, naphthyl, thienyl, furanyl, indolyl, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl,isoxazolyl, benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl, piperidinyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,S,S-dioxothiomorpholinyl, or C₃-C₈ cycloalkyl, each of which isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, phenyl,naphthyl, wherein the phenyl and naphthyl groups are optionallysubstituted with 1 or more groups that are independently selected fromC₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, CF₃, and OCF₃, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆alkanoyl, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, whereineach R₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl, C₁-C₆alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆alkyl) (C₁-C₆ alkyl); R₁₀ is C₂-C₆ alkenyl, C₂-C₆ alkynyl, phenyl,naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl, C₃-C₈cycloalkyl, wherein the cyclic portions are optionally substituted withhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄ haloalkyl,or C₁-C₄ haloalkoxy; wherein the heterocycloalkyl and the cycloalkylportions of R₁ and R₁₀ are further optionally substituted with ═O,═N—OH, or ═N—OCH₃; and R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄alkoxy C₁-C₆ alkyl, C₂-C₆ alkynyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkyl C₁-C₆ alkyl, C₃-C₈ cycloalkyl C₂-C₆ alkenyl, cycloalkylC₂-C₆ alkynyl, piperidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl,thiomorpholinyl, S,S-dioxothiomorpholinyl, tetrahydrofuranyl,tetrahydrothienyl, morpholinyl C₁-C₆ alkyl, thiomorpholinyl C₁-C₆ alkyl,S,S-dioxothiomorpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl,pyrrolidinyl C₁-C₆ alkyl, imidazolidinyl C₁-C₆ alkyl, piperidinyl C₂-C₆alkenyl, pyrrolidinyl C₂-C₆ alkenyl, imidazolidinyl C₂-C₆ alkenyl,morpholinyl C₂-C₆ alkenyl, thiomorpholinyl C₂-C₆ alkenyl,S,S-dioxothiomorpholinyl C₂-C₆ alkenyl, tetrahydrofuranyl C₂-C₆ alkenyl,tetrahydrothienyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinylC₂-C₆ alkynyl, imidazolidinyl C₂-C₆ alkynyl, morpholinyl C₂-C₆ alkynyl,thiomorpholinyl C₂-C₆ alkynyl, S,S-dioxothiomorpholinyl C₂-C₆ alkynyl,tetrahydrofuranyl C₂-C₆ alkynyl, tetrahydrothienyl C₂-C₆ alkynyl,phenyl, naphthyl, furanyl, pyridyl, pyrimidyl, pyrazinyl, thienyl,imidazolyl, pyrazinyl C₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, pyrimidyl C₁-C₆alkyl, pyrazinyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆alkyl, thienyl C₁-C₆ alkyl, heteroarylalkenyl, heteroarylalkynyl, phenylC₁-C₆ alkyl, naphthyl C₁-C₆ alkyl, phenyl C₂-C₆ alkenyl, naphthyl C₂-C₆alkenyl, phenyl C₂-C₆ alkynyl, naphthyl C₂-C₆ alkynyl, wherein thecyclic portion of each of the above is unsubstituted or substituted withone or more groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, —SO₂-(C₁-C₆) alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN,OH, phenyl C₁-C₆ alkyl wherein the phenyl is optionally substituted with1, 2, 3, 4, or 5 groups that are independently selected from C₁-C₄alkyl, C₁-C₄ alkoxy, CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈,wherein R₇ and R₈ are independently H or C₁-C₆ alkyl, wherein the C₁-C₆alkyl is optionally substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆ alkoxy, C₁-C₆alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H;wherein the heterocycloalkyl and the cycloalkyl portions of the aboveare further optionally substituted with ═O, ═N—OH, or ═N—OCH₃; or R₄ andR₅ and the nitrogen to which they are attached form a piperazinyl,morpholinyl, piperidinyl, thiomorpholinyl, imidazolidinyl,S,S,-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, ring, which isunsubstituted or substituted with 1 or more groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, phenyl C₁-C₆ alkyl,naphthyl C₁-C₆ alkyl, C₁-C₆ alkanoyl, OH, ═O, pyridyl, pyrimidyl,pyrazinyl, pyrimidyl C₁-C₆ alkyl, pyrazinyl C₁-C₆ alkyl, phenyl,naphthyl, —OCH₂CH₂O—, —OCH₂O—, wherein the pyridyl, pyrimidyl,pyrazinyl, pyrimidyl C₁-C₆ alkyl, phenyl and naphthyl groups areunsubstituted or substituted with 1 or more groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.
 5. Acompound according to claim 4, wherein R₂ and R₃ are independently H,halogen, or C₁-C₆ alkyl.
 6. A compound according to claim 5, wherein Zis a bond, —CH₂—, or —NH—.
 7. A compound according to claim 6, whereinR₁ is C₂-C₆ alkynyl, phenyl, thienyl, pyridyl, triazolyl, imidazolyl,pyrazinyl, benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl, each of whichis unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, phenyl,wherein the phenyl is optionally substituted with 1 or more groups thatare independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,CF₃, and OCF₃, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, —OC(O)—C₁-C₆ alkyl,C₁-C₆ alkoxycarbonyl, C₁-C₆ alkanoyl, —C(O)R₁₀, or, NR₆R₇, —(C₁-C₄alkyl)-NR₆R₇, —C(O)NR₆R₇, wherein each R₆ and R₇ is independently H,C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl, C₁-C₆ alkoxycarbonyl, wherein the alkylportion of each is unsubstituted or substituted with 1, 2, or 3, groupsthat are independently halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); and R₁₀ is phenyl,pyridyl, or C₃-C₈ cycloalkyl, wherein the cyclic portions are optionallysubstituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂,C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy.
 8. A compound according to claim7, wherein R₄ and R₅ are independently H, C₁-C₆ alkyl, C₁-C₄ alkoxyC₁-C₆ alkyl, C₃-C₈ cycloalkyl, piperidinyl, pyrrolidinyl, morpholinyl,morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆ alkyl, pyrrolidinyl C₁-C₆alkyl, piperidinyl C₂-C₆ alkenyl, pyrrolidinyl C₂-C₆ alkenyl,morpholinyl C₂-C₆ alkenyl, piperidinyl C₂-C₆ alkynyl, pyrrolidinyl C₂-C₆alkynyl, morpholinyl C₂-C₆ alkynyl, phenyl, furanyl, pyridyl, pyrazinylC₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₆alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, phenyl C₂-C₆ alkenyl,phenyl C₂-C₆ alkynyl, wherein the cyclic portion of each of the above isunsubstituted or substituted with one or more groups that areindependently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₆) alkyl,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NO₂, CN, OH, phenyl C₁-C₆ alkylwherein the phenyl is optionally substituted with 1, 2, 3, 4, or 5groups that are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,CN, halogen, OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, C₁-C₆ alkanoyl, NR₇R₈, or —C(O)NR₇R₈, wherein R₇ and R₈are independently H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl isoptionally substituted with 1, 2, or 3 groups that are independentlyC₁-C₆ alkoxycarbonyl, halogen, C₁-C₆ alkoxy, C₁-C₆ alkanoyl, NH₂,NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆ alkyl) or CO₂H; wherein theheterocycloalkyl and the cycloalkyl portions of R₄ and R₅ are furtheroptionally substituted with ═O, ═N—OH, or ═N—OCH₃.
 9. A compoundaccording to claim 8, wherein Z is —NH— or —CH₂—; R₁ is C₂-C₆ alkynyl,phenyl, thienyl, pyridyl, triazolyl, imidazolyl, pyrazinyl,benzofuranyl, 3,4-dihydropyrimidin-2(1H)-onyl, each of which isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, phenyl,wherein the phenyl is optionally substituted with 1 or more groups thatare independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,CF₃, and OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,C₁-C₆ alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein eachR₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl, C₁-C₆alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted orsubstituted with 1, 2, or 3, groups that are independently halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆alkyl) (C₁-C₆ alkyl); and and R₄ and R₅ are independently H, C₁-C₆alkyl, C₁-C₄ alkoxy C₁-C₆ alkyl, C₃-C₈ cycloalkyl, piperidinyl,pyrrolidinyl, morpholinyl, morpholinyl C₁-C₆ alkyl, piperidinyl C₁-C₆alkyl, pyrrolidinyl C₁-C₆ alkyl, phenyl, furanyl, pyridyl, pyrazinylC₁-C₆ alkyl, pyridyl C₁-C₆ alkyl, imidazolyl C₁-C₆ alkyl, furanyl C₁-C₄alkyl, thienyl C₁-C₆ alkyl, phenyl C₁-C₆ alkyl, wherein the cyclicportion of each of the above is unsubstituted or substituted with one ormore groups that are independently C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen,—SO₂—(C₁-C₆) alkyl, CF₃, OCF₃, NO₂, CN, OH, phenyl C₁-C₆ alkyl whereinthe phenyl is optionally substituted with 1, 2, 3, 4, or 5 groups thatare independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, halogen,OH, and alkanoyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆alkanoyl, NR₇R₈, or —C(O)NR₇R₈, wherein R₇ and R₈ are independently H orC₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with 1,2, or 3 groups that are independently C₁-C₆ alkoxycarbonyl, halogen,C₁-C₆ alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl)(C₁-C₆ alkyl) or CO₂H; wherein the heterocycloalkyl and the cycloalkylportions of R₄ and R₅ are further optionally substituted with ═O, ═N—OH,or ═N—OCH₃.
 10. A compound according to claim 9, wherein R₁ is phenyl,thienyl, pyridyl, imidazolyl, pyrazinyl, benzofuranyl, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, phenyl,wherein the phenyl is optionally substituted with 1 or more groups thatare independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,CF₃, and OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₆ alkyl, C₁-C₆ alkoxycarbonyl,C₁-C₆ alkanoyl, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein eachR₆ and R₇ is independently H, C₁-C₆ alkyl, or C₁-C₆ alkoxycarbonyl,wherein the alkyl portion of each is unsubstituted or substituted with1, 2, or 3, groups that are independently halogen, OH, CF₃, OCF₃, NH₂,NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); and and R₄ and R₅ areindependently H, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, piperidinyl,pyrrolidinyl, morpholinyl C₁-C₄ alkyl, piperidinyl C₁-C₄ alkyl, phenyl,furanyl, pyridyl, pyrazinyl C₁-C₄ alkyl, pyridyl C₁-C₄ alkyl, imidazolylC₁-C₄ alkyl, furanyl C₁-C₄ alkyl, thienyl C₁-C₄ alkyl, phenyl C₁-C₄alkyl, wherein the cyclic portion of each of the above is unsubstitutedor substituted with one or more groups that are independently C₁-C₆alkyl, C₁-C₆ alkoxy, halogen, —SO₂—(C₁-C₄) alkyl, CF₃, OCF₃, NO₂, CN,OH, NR₇R₈, or —C(O)NR₇R₈, wherein R₇ and R₈ are independently H or C₁-C₆alkyl, wherein the C₁-C₆ alkyl is optionally substituted with 1, or 2groups that are independently C₁-C₆ alkoxycarbonyl, halogen, C₁-C₆alkoxy, C₁-C₆ alkanoyl, NH₂, NH(C₁-C₆ alkyl), N(C₁-C₆ alkyl) (C₁-C₆alkyl) or CO₂H; wherein the heterocycloalkyl and the cycloalkyl portionsof R₄ and R₅ are further optionally substituted with ═O, ═N—OH, or═N—OCH₃.
 11. A compound according to claim 10, wherein R₄ is H ormethyl; and R₅ is —CH₂-furanyl.
 12. A compound according to claim 11,wherein R₁ is phenyl, thienyl, pyridyl, or pyrazinyl, each of which isunsubstituted or substituted with 1, 2, or 3 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CF₃, OCF₃, NR₆R₇,—(C₁-C₂ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein each R₆ and R₇ at eachoccurrence are independently H, C₁-C₆ alkyl, or C₁-C₄ alkoxycarbonyl.13. A compound according to claim 6, wherein R₄ and R₅ and the nitrogento which they are attached form a piperazinyl, morpholinyl, piperidinyl,imidazolidinyl, or pyrrolidinyl ring, each of which is unsubstituted orsubstituted with 1 or more groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, phenyl C₁-C₄ alkyl, C₁-C₆ alkanoyl, OH, pyridyl,pyrimidyl, pyrazinyl, pyrimidyl C₁-C₄ alkyl, pyrazinyl C₁-C₄ alkyl,phenyl, —OCH₂CH₂O—, —OCH₂O—, wherein the pyridyl, pyrimidyl, pyrazinyl,pyrimidyl C₁-C₆ alkyl, and phenyl groups are unsubstituted orsubstituted with 1 or more groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, CF₃ or OCF₃.
 14. A compound according to claim13, wherein R₁ is phenyl, thienyl, furanyl, pyridyl, pyrazinyl,triazolyl, imidazolyl, oxazolyl, benzofuranyl, each of which isunsubstituted or substituted with 1, 2, 3, 4, or 5 groups that areindependently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy, OH, CN, CO₂H, phenyl,wherein the phenyl group is optionally substituted with 1 or more groupsthat are independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen,OH, CF₃, and OCF₃, CF₃, OCF₃, —OC(O)—C₁-C₄ alkyl, C₁-C₄ alkoxycarbonyl,or C₁-C₄ alkanoyl.
 15. A compound according to claim 13, wherein R₁ isphenyl, thienyl, pyridyl, pyrazinyl, triazolyl, imidazolyl,benzofuranyl, each of which is unsubstituted or substituted with 1, 2,or 3 groups that are independently C₁-C₆ alkyl, halogen, C₁-C₆ alkoxy,OH, —C(O)R₁₀, NR₆R₇, —(C₁-C₄ alkyl)-NR₆R₇, or —C(O)NR₆R₇, wherein eachR₆ and R₇ is independently H, C₁-C₆ alkyl, C₁-C₄ alkoxyalkyl, C₁-C₆alkoxycarbonyl, wherein the alkyl portion of each is unsubstituted orsubstituted with 1, or 2 groups that are independently halogen, OH, CF₃,OCF₃, NH₂, NH(C₁-C₆ alkyl) or N(C₁-C₆ alkyl) (C₁-C₆ alkyl); R₁₀ isphenyl, naphthyl, pyridyl, quinolinyl, pyrimidyl, furanyl, indolyl, orC₃-C₈ cycloalkyl, each of which is optionally substituted with halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, OH, CO₂H, CN, NO₂, C₁-C₄ haloalkyl, or C₁-C₄haloalkoxy; wherein the heterocycloalkyl and the cycloalkyl portions ofR₁ and R₁₀ are further optionally substituted with ═O, ═N—OH, or═N—OCH₃.
 16. A compound according to claim 15, wherein R₄ and R₅ and thenitrogen to which they are attached form a piperazinyl, morpholinyl,piperidinyl, imidazolidinyl, or pyrrolidinyl ring, which isunsubstituted or substituted with 1 or more groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, phenyl C₁-C₂ alkyl,C₁-C₆ alkanoyl, OH, pyridyl, pyrimidyl C₁-C₂ alkyl, phenyl, —OCH₂CH₂O—,or —OCH₂O—; and R₂ and R₃ are both H.
 17. A compound according to claim1 which is8-[5-(2-Dimethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-carboxylicacid (furan-2-ylmethyl)-amide;8-[5-(2-Diethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-carboxylicacid (furan-2-ylmethyl)-amide;8-[5-(2-Dimethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-carboxylicacid cyclopropylamide;8-[5-(2-Diethylamino-ethylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-carboxylicacid cyclopropylamide;5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic acidamide;5-(2-Methylcarbamoyl-[1,6]naphthyridin-8-yl)-thiophene-2-carboxylic acidmethylamide;8-[5-(3-Morpholin-4-yl-propylcarbamoyl)-thiophen-2-yl]-[1,6]naphthyridine-2-carboxylicacid methylamide; 8-Thiophen-3-yl[1,6]-naphthyridine-2-carboxylic acid;8-Thiophen-3-yl[1,6]-naphthyridine-2-carboxylic acid(2-oxo-cyclohexyl)amide; 8-Thiophen-3-yl-[1,6]naphthyridine-2-carboxylicacid amide; 8-Phenyl[1,6]-naphthyridine-2-carboxylic acid;8-Phenyl[1,6]-naphthyridine-2-carboxylic acid amide;8-Phenyl[1,6]-naphthyridine-2-carboxylic acid (2-oxo-cyclohexyl)amide;8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acidcyclopropylamide;8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acid amide;8-(3-Hydroxy-prop-1-ynyl-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)amide;(3-{2-[(Furan-2-ylmethyl)-carbamoyl]-[1,6]naphthyridin-8-yl}-prop-2-ynyl)-carbamicacid tert-butyl ester; 8-Phenylethynyl-[1,6]naphthyridine-2-carboxylicacid (furan-2-ylmethyl)-amide; 8-Ethynyl-[1,6]naphthyridine-2-carboxylicacid (furan-2-ylmethyl)-amide;8-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-para-Tolylamino-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide; 8-Phenylamino-[1,6]naphthyridine-2-carboxylicacid (furan-2-ylmethyl)-amide;8-(3-Trifluoromethyl-phenylamino0-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(4-Trifluoromethyl-phenylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(Pyridin-3-ylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(Pyridin-4-ylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(Pyrazin-2-ylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(3,5-Dichloro-phenylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylic acidcyclopropylamide;8-(3,5-Dichloro-phenylamino)-[1,6]naphthyridine-2-carboxylic acidcyclopropylamide;8-(4-Methoxy-phenylamino)-[1,6]naphthyridine-2-carboxylic acid amide;8-[(Furan-2-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-[(Pyridin-4-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-[(Pyridin-2-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-[(Pyridin-3-ylmethyl)-amino]-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(3-Methoxy-benzylamino)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-Cyclopropylamino-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-Prop-2-ynylamino-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide;8-(2-Oxo-pyrrolidin-1-yl)-[1,6]naphthyridine-2-carboxylic acid(furan-2-ylmethyl)-amide; 8-(3-thienyl)-1,6-naphthyridine-2-carboxylicacid;N-cyclopropyl-8-[5-({[2-(diethylamino)ethyl]amino}carbonyl)-2-thienyl]-1,6-naphthyridine-2-carboxamide;8-phenyl-1,6-naphthyridine-2-carboxylic acid;N-(2-furylmethyl)-8-{[4-(trifluoromethyl)phenyl]amino}-1,6-naphthyridine-2-carboxamide;N-(2-furylmethyl)-8-[(4-methylphenyl)amino]-1,6-naphthyridine-2-carboxamide;8-anilino-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide;N-(2-furylmethyl)-8-{[3-(trifluoromethyl)phenyl]amino}-1,6-naphthyridine-2-carboxamide;N-(2-furylmethyl)-8-[(4-methoxyphenyl)amino]-1,6-naphthyridine-2-carboxamide;N-(2-furylmethyl)-8-(3-hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2-carboxamide;8-(5-carboxy-2-thienyl)-1,6-naphthyridine-2-carboxylic acid;N-(2-furylmethyl)-8-(pyridin-3-ylamino)-1,6-naphthyridine-2-carboxamide;tert-butyl[3-(2-{[(2-furylmethyl)amino]carbonyl}-1,6-naphthyridin-8-yl)prop-2-yn-1-yl]carbamate;N-(2-furylmethyl)-8-(pyridin-4-ylamino)-1,6-naphthyridine-2-carboxamide;8-[5-({[2-(diethylamino)ethyl]amino}carbonyl)-2-thienyl]-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide;8-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-2-thienyl]-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide;N-cyclopropyl-8-[5-({[2-(dimethylamino)ethyl]amino}carbonyl)-2-thienyl]-1,6-naphthyridine-2-carboxamide;N-(2-furylmethyl)-8-(pyrazin-2-ylamino)-1,6-naphthyridine-2-carboxamide;N-(2-oxocyclohexyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide;N-(2-oxocyclohexyl)-8-phenyl-1,6-naphthyridine-2-carboxamide;8-(3-hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2-carboxamide;N-cyclopropyl-8-(3-hydroxyprop-1-yn-1-yl)-1,6-naphthyridine-2-carboxamide;N-(2-furylmethyl)-8-(phenylethynyl)-1,6-naphthyridine-2-carboxamide;8-ethynyl-N-(2-furylmethyl)-1,6-naphthyridine-2-carboxamide;N-cyclopropyl-8-[(4-methoxyphenyl)amino]-1,6-naphthyridine-2-carboxamide;2-[(4-benzylpiperazin-1-yl)carbonyl]-8-(4-methoxyphenyl)-1,6-naphthyridine;N-[4-(methylsulfonyl)benzyl]-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide;1-{[8-(3-thienyl)-1,6-naphthyridin-2-yl]carbonyl}piperidin-4-ol;N-(2-methoxyethyl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide;8-(4-methoxyphenyl)-2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1,6-naphthyridine;N-(1-benzylpiperidin-4-yl)-8-(4-methoxyphenyl)-1,6-naphthyridine-2-carboxamide;8-(4-methoxyphenyl)-N-[4-(methylsulfonyl)benzyl]-1,6-naphthyridine-2-carboxamide;2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-8-phenyl-1,6-naphthyridine;8-phenyl-2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-1,6-naphthyridine;2-[(4-benzylpiperazin-1-yl)carbonyl]-8-phenyl-1,6-naphthyridine;N-(1-benzylpiperidin-4-yl)-8-phenyl-1,6-naphthyridine-2-carboxamide;N-[4-(methylsulfonyl)benzyl]-8-phenyl-1,6-naphthyridine-2-carboxamide;2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-8-(3-thienyl)-1,6-naphthyridine;2-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]-8-(3-thienyl)-1,6-naphthyridine;2-[(4-benzylpiperazin-1-yl)carbonyl]-8-(3-thienyl)-1,6-naphthyridine;N-(1-benzylpiperidin-4-yl)-8-(3-thienyl)-1,6-naphthyridine-2-carboxamide;2-({4-[(4,6-dimethoxypyrimidin-2-yl)methyl]piperazin-1-yl}carbonyl)-8-(3-thienyl)-1,6-naphthyridine;1-{[8-(1-benzofuran-2-yl)-1,6-naphthyridin-2-yl]carbonyl}piperidin-4-ol;8-(1-benzofuran-2-yl)-N-(2-methoxyethyl)-1,6-naphthyridine-2-carboxamide;1-[(8-phenyl-1,6-naphthyridin-2-yl)carbonyl]piperidin-4-ol;N-(2-methoxyethyl)-8-phenyl-1,6-naphthyridine-2-carboxamide;8-(1-benzofuran-2-yl)-2-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)-1,6-naphthyridine;8-(1-benzofuran-2-yl)-2-[(4-benzylpiperazin-1-yl)carbonyl]-1,6-naphthyridine;8-(1-benzofuran-2-yl)-N-(1-benzylpiperidin-4-yl)-1,6-naphthyridine-2-carboxamide;8-(1-benzofuran-2-yl)-N-[4-(methylsulfonyl)benzyl]-1,6-naphthyridine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound according to claim 1 and at least onepharmaceutically acceptable solvent, carrier, excipient, adjuvant or acombination thereof.
 19. A method of treating a disease or conditionselected from inflammation and arthritis comprising administering atherapeutically effective amount of a compound of claim 1 to a patientin need of such treatment.